New ccr2 receptor antagonists and uses thereof

ABSTRACT

The present invention relates to novel antagonists for CCR2 (CC chemokine receptor 2) and their use for providing medicaments for treating conditions and diseases, especially pulmonary diseases like asthma and COPD.

FIELD OF INVENTION

The present invention relates to novel antagonists for CCR2 (CCchemokine receptor 2) and their use for providing medicaments fortreating conditions and diseases where activation of CCR2 plays acausative role, especially pulmonary diseases like asthma and COPD,neurologic disease, especially of pain diseases, immune relateddiseases, especially diabetes mellitus including diabetes nephropathy,and cardiovascular diseases, especially atherosclerotic disease.

BACKGROUND OF THE INVENTION

The chemokines are a family of small, proinflammatory cytokines, withpotent chemotatctic activities. Chemokines are chemotactic cytokinesthat are released by a wide variety of cells to attract various cells,such as monocytes, macrophages, T cells, eosinophils, basophils andneutrophils to sites of inflammation.

Chemokine receptors, such as CCR2 or CCR5 have been implicated as beingimportant mediators of inflammatory and immunoregulatory disorders anddiseases as well as autoimmune pathologies such as rheumatoid arthritisand atherosclerosis. Accordingly, agents which modulate chemokinereceptors such as the CCR2 and CCR5 receptor would be useful in suchdisorders and diseases.

In particular it is widely accepted that numerous conditions anddiseases involve inflammatory processes. Such inflammations arecritically triggered and/or promoted by the activity of macrophages,which are formed by differentiation out of monocytes. It has furtherbeen found that monocytes are characterized by, e.g., a high expressionof membrane-resident CCR2, whereas the CCR2 expression in macrophages islower. CCR2 is a critical regulator of monocytes trafficking, which canbe described as the movement of the monocytes towards an inflammationalong a gradient of monocyte chemoattractant proteins (MCP-1, MCP-2,MCP-3, MCP-4).

Therefore, in order to reduce macrophage-induced inflammation, it wouldbe desirable to block the monocyte CCR2 by an antagonist, so that themonocytes can be less triggered to move towards an inflammation area forconversion into macrophages.

Based on the aforesaid there is a need for providing effectiveantagonists for CCR2, which are pharmacologically acceptable.

DESCRIPTION OF THE INVENTION

It has now been found that such effective CCR2 inhibitors can beprovided by compounds according to general formula (I),

wherein R₁ is a group selected from among —H, -halogen, —CN,—O—C₁-C₄-alkyl, —C₁-C₄-alkyl, —CH═CH₂, —C≡CH, —CF₃, —OCF₃, —OCF₂H, and—OCFH₂;

wherein R₇ is a ring selected from among —C₃-C₈-cycloalkyl,—C₃-C₈-heterocyclyl, —C₅-C₁₀-aryl, and —C₅-C₁₀-heteroaryl,

wherein the ring R₇ is optionally substituted with one or more groupsselected from among —CF₃, —O—CF₃, —S—CF₃, —CN, —C₁-C₆-alkyl,—C(CH₃)₂—CN, and -halogen,

or wherein the ring R₇ is optionally substituted with one or more groupsselected from among —C₁-C₆-alkyl, —O—C₁-C₆-alkyl, —C₅-C₁₀-aryl,—C₅-C₁₀-heteroaryl, —C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl,—C₂-C₆-alkenyl, and —C₂-C₆-alkynyl, optionally being substituted by oneor more groups selected from among —OH, —NH₂, —C₁-C₃-alkyl,—O—C₁-C₆-alkyl, —CN, —CF₃, —OCF₃, halogen, -methyl, and αO,

or wherein the ring R₇ is optionally further bi-valently substituted ontwo neighbouring ring atoms, such that an annellated ring is formed byone or more groups selected from among —C₁-C₆-alkylene,—C₂-C₆-alkenylene and —C₄-C₆-alkynylene, in which one or two or threecarbon centers may optionally be replaced by 1 or 2 or 3 hetero atomsselected from N, O and S, the bivalent group being optionallysubstituted by one or more groups selected from —OH, —NH₂, —C₁-C₃-alkyl,—O—C₁-C₆-alkyl, —CN, —CF₃, —OCF₃, halogen, and ═O;

wherein R₂ is selected from among —H, -halogen, —CN, —O—C₂-C₄-alkyl,—C₁-C₄-alkyl, —CH═CH₂, —C≡CH, —CF₃, —OCF₃, —OCF₂H, and —OCFH₂;

wherein R₃ is selected from among —H, -methyl, -ethyl, -propyl,-i-propyl, -cyclopropyl, —OCH₃, —CF₃, and —CN;

wherein n is 1, 2 or 3;

wherein G and E are independently selected from among C—H or N;

wherein Z is C,

and R₄ and R₅ are independently selected from among —H, —C₁-C₆-alkyl,—NH₂, —C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl, —C₅-C₁₀-aryl,—C₅-C₁₀-heteroaryl, and —C(O)—N(R₈,R₈′), with R₈ and R₈′ independentlybeing selected from among —H, and —C₁-C₆-alkyl,

or wherein Z is N,

and R₄ denotes an electron pair and R₅ is selected from among —H,—C₁-C₆-alkyl, —NH₂, —C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl,—C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl, and —C(O)—N(R₈,R₈′), with R₈ and R₈′independently being selected from among —H, and —C₁-C₆-alkyl

and wherein R₄ and R₅ if different from an electron pair or —H areoptionally independently substituted with one or more groups selectedfrom among -halogen, —OH, —CF₃, —CN, —C₁-C₆-alkyl, —O—C₁-C₆-alkyl,—O—C₃-C₈-cycloalkyl, —O—C₃-C₈-heterocyclyl, —O—C₅-C₁₀-aryl,—O—C₅-C₁₀-heteroaryl, —C₀-C₆-alkylene-CN, —C₀-C₄-alkylene-O—C₁-C₄-alkyl,—C₀-C₄-alkylene-O—C₃-C₈-cycloalkyl,—C₀-C₄-alkylene-O—C₃-C₈-heterocyclyl, —C₀-C₄-alkylene-O—C₅-C₁₀-aryl,—C₀-C₄-alkylene-O—C₅-C₁₀-heteroaryl,—C₀-C₄-alkylene-Q-C₀-C₄-alkyl-N(R₉,R₉′),—C₀-C₄-alkylene-N(R₁₀)-Q-C₁-C₄-alkyl,—C₀-C₄-alkylene-N(R₁₀)-Q-C₃-C₈-cycloalkyl,—C₀-C₄-alkylene-N(R₁₀)-Q-C₃-C₈-heterocyclyl,—C₀-C₄-alkylene-N(R₁₀)-Q-C₅-C₁₀-aryl,—C₀-C₄-alkylene-N(R₁₀)-Q-C₅-C₁₀-heteroaryl,—C₀-C₄-alkylene-Q-N(R₁₁,R₁₁′), —C₀-C₄-alkylene-N(R₁₂)-Q-N(R₁₃,R₁₃′),—C₀-C₄-alkylene-R₁₄, —C₀-C₄-alkylene(R₂₀,R₂₀′),—C₀-C₄-alkylene-Q-C₁-C₆-alkyl, —C₀-C₄-alkylene-Q-C₃-C₈-cycloalkyl,—C₀-C₄-alkylene-Q-C₃-C₈-heterocyclyl, —C₀-C₄-alkylene-Q-C₅-C₁₀-aryl,—C₀-C₄-alkylene-Q-C₅-C₁₀-heteroaryl, —C₀-C₄-alkylene-O-Q-N(R₁₅,R₁₅′),and —C₀-C₄-alkylene-N(R₁₆)-Q-O—(R₁₇),

wherein Q is selected from among —C(O)—, and —SO₂—,

wherein R₁₀, R₁₂, R₁₆, are independently selected from among —H,—C₁-C₆-alkyl, and —C₃-C₆-cycloalkyl,

wherein R₉, R₉′, R₁₁, R₁₁′, R₁₃, R₁₃′, R₁₅, R₁₅′, are independentlyselected from among —H, —C₁-C₆-alkyl, and —C₃-C₆-cycloalkyl,

or wherein R₉ and R₉′, R₁₁ and R₁₁′, R₁₃ and R₁₃′, R₁₅ and R₁₅′ togetherform a —C₂-C₆-alkylene group,

wherein R₁₄ and R₁₇ are independently selected from among —H,—C₁-C₆-alkyl, —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl, —C₃-C₈-cycloalkyl, and—C₃-C₈-heterocyclyl, wherein said —C₃-C₈-heterocyclyl optionallycomprises nitrogen and/or —SO₂— in the ring,

and wherein R₁₄ and R₁₇ are optionally substituted with one or moregroups selected from among —OH, —OCH₃, —CF₃, —COOH, —OCF₃, —CN,-halogen, —C₁-C₄-alkyl, ═O, and —SO₂—C₁-C₄-alkyl,

wherein R₂₀ and R₂₀′ together form a spiro-C₃-C₈-cycloalkylcycle orspiro-C₃-C₈-heterocycle comprising one or more group selected from O inthe ring, and wherein said spirocycle is optionally further bi-valentlysubstituted by an annellated ring forming group selected from among—C₁-C₆-alkylene, —C₂-C₆-alkenylene, and —C₄-C₆-alkynylene and whereinsaid spirocycle is optionally further substituted with one or moregroups selected from among —OH, —OCH₃, —CF₃, —COOH, —OCF₃, —CN,-halogen,

or wherein Z is C,

and R₄ denotes —H, and R₅ is selected from a group of the structure-L₁-R₁₈,

wherein L₁ is selected from among —NH— and —N(C₁-C₄-alkyl)-, and a bond,

wherein R₁₈ is selected from among —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl,—C₃-C₈-cycloalkyl, and —C₃-C₈-heterocyclyl,

wherein R₁₈ is optionally substituted by one or more groups selectedfrom among halogen, —CF₃, —OCF₃, —CN, —OH, —O—C₁-C₄-alkyl, —C₁-C₆-alkyl,—NH—C(O)—C₁-C₆-alkyl, —N(C₁-C₄-alkyl)-C(O)—C₁-C₆-alkyl,—C(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl, —NH—S(O)₂—C₁-C₆-alkyl,—N(C₁-C₄-alkyl)-S(O)₂—C₁-C₆-alkyl, and —C(O)—O—C₁-C₆-alkyl, and whereinR₄, R₅ and R₁₈ are optionally further substituted byspiro-C₃-C₈-cycloalkyl or spiro-C₃-C₈-heterocyclyl such that togetherwith R₄, R₅ and/or R₁₈ a spirocycle is formed, wherein saidspiro-C₃-C₈-heterocyclyl optionally comprises one or more groupsselected from among nitrogen, —C(O)—, —SO₂—, and —N(SO₂—C₁-C₄-alkyl)- inthe ring,

or wherein R₄, R₅ and R₁₈ are optionally further bi-valently substitutedby one or more spirocyclic or annellated ring forming groups selectedfrom among —C₁-C₆-alkylene, —C₂-C₆-alkenylene, and —C₄-C₆-alkynylene, inwhich one or two carbon centers may optionally be replaced by one or twohetero atoms selected from among N, O and S and which may optionally besubstituted by one or more groups on one ring atom or on twoneighbouring ring atoms selected from among —OH, —NH₂, —C₁-C₃-alkyl,—O—C₁-C₆-alkyl, —CN, —CF₃, —OCF₃, and halogen;

wherein R₆ is selected from among —H, —C₁-C₄-alkyl, —OH, —O—C₁-C₄-alkyl,-halogen, —CN, —CF₃, and —OCF₃;

as well as in form of their acid addition salts with pharmacologicallyacceptable acids, as well as in form of their solvates and/or hydrates.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, L₁, E, G, Z,Q, and n as herein before or below defined, wherein R₇ is a ringselected from among —C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl,—C₅-C₁₀-aryl, and —C₅-C₁₀-heteroaryl, wherein the ring R₇ is optionallysubstituted with one or more groups selected from among —CF₃, —O—CF₃,—CN, —C₁-C₆-alkyl, —C(CH₃)₂—CN, and -halogen,

or wherein the ring R₇ is optionally substituted with one or more groupsselected from among —C₁-C₆-alkyl, —O—C₁-C₆-alkyl, —C₅-C₁₀-aryl,—C₅-C₁₀-heteroaryl, —C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl,—C₂-C₆-alkenyl, and —C₂-C₆-alkynyl, optionally being substituted by oneor more groups selected from among —OH, —NH₂, —C₁-C₃-alkyl,—O—C₁-C₆-alkyl, —CN, —CF₃, —OCF₃, halogen, -methyl, and ═O,

or wherein the ring R₇ is optionally further bi-valently substituted ontwo neighbouring ring atoms, such that an annellated ring is formed byone or more groups selected from among —C₁-C₆-alkylene,—C₂-C₆-alkenylene and —C₄-C₆-alkynylene, in which one or two or threecarbon centers may optionally be replaced by 1 or 2 or 3 hetero atomsselected from N, O and S, the bivalent group being optionallysubstituted by one or more groups selected from —OH, —NH₂, —C₁-C₃-alkyl,—O—C₁-C₆-alkyl, —CN, —CF₃, —OCF₃, halogen, and ═O.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₁₉, R₁₉′, E, G, Q, and n as hereinbefore or below defined,

wherein Z is C,

and R₄ and R₅ are independently selected from —H, —C₁-C₆-alkyl, —NH₂,—C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl, —C₅-C₁₀-aryl,—C₅-C₁₀-heteroaryl, and —C(O)—N(R₈,R₈′), with R₈ and R₈′ independentlybeing selected from among —H, and —C₁-C₆-alkyl,

and wherein R₄ and R₅ if different from —H are optionally independentlysubstituted with one or more groups selected from among -halogen, —OH,—CF₃, —CN, —C₁-C₆-alkyl, —O—C₁-C₆-alkyl, —O—C₃-C₈-cycloalkyl,—O—C₃-C₈-heterocyclyl, —O—C₅-C₁₀-aryl, —O—C₅-C₁₀-heteroaryl,—C₀-C₆-alkylene-CN, —C₀-C₄-alkylene-O—C₁-C₄-alkyl,—C₀-C₄-alkylene-O—C₃-C₈-cycloalkyl,—C₀-C₄-alkylene-O—C₃-C₈-heterocyclyl, —C₀-C₄-alkylene-O—C₅-C₁₀-aryl,—C₀-C₄-alkylene-O—C₅-C₁₀-heteroaryl,—C₀-C₄-alkylene-Q-C₀-C₄-alkyl-N(R₉,R₉′),—C₀-C₄-alkylene-N(R₁₀)-Q-C₁-C₄-alkyl,—C₀-C₄-alkylene-N(R₁₀)-Q-C₃-C₈-cycloalkyl,

—C₀-C₄-alkylene-N(R₁₀)-Q-C₃-C₈-heterocyclyl,—C₀-C₄-alkylene-N(R₁₀)-Q-C₅-C₁₀-aryl,—C₀-C₄-alkylene-N(R₁₀)-Q-C₅-C₁₀-heteroaryl,—C₀-C₄-alkylene-Q-N(R₁₁,R₁₁′), —C₀-C₄-alkylene-N(R₁₂)-Q-N(R₁₃,R₁₃′),—C₀-C₄-alkylene-R₁₄, —C₀-C₄-alkylene-Q-C₁-C₆-alkyl,—C₀-C₄-alkylene-Q-C₃-C₈-cycloalkyl,—C₀-C₄-alkylene-Q-C₃-C₈-heterocyclyl, —C₀-C₄-alkylene-Q-C₅-C₁₀-aryl,—C₀-C₄-alkylene-Q-C₅-C₁₀-heteroaryl, —C₀-C₄-alkylene-O-Q-N(R₁₅,R₁₅′),and —C₀-C₄-alkylene-N(R₁₆)-Q-O-(R₁₇),

wherein Q is selected from among —C(O)—, and —SO₂—,

wherein R₁₀, R₁₂, R₁₆, are independently selected from among —H,—C₁-C₆-alkyl, and —C₃-C₆-cycloalkyl,

wherein R₉, R₉′, R₁₁, R₁₁′, R₁₃, R₁₃′, R₁₅, R₁₅′, are independentlyselected from among —H, —C₁-C₆-alkyl, and —C₃-C₆-cycloalkyl,

or wherein R₉ and R₉′, R₁₁ and R₁₁′, R₁₃ and R₁₃′, R₁₅ and R₁₅′ togetherform a —C₂-C₆-alkylene group,

wherein R₁₄ and R₁₇ are independently selected from among —H,—C₁-C₆-alkyl, —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl, —C₃-C₈-cycloalkyl, and—C₃-C₈-heterocyclyl, wherein said —C₃-C₈-heterocyclyl optionallycomprises nitrogen and/or —SO₂— in the ring,

and wherein R₁₄ and R₁₇ are optionally substituted with one or moregroups selected from among —OH, —OCH₃, —CF₃, —OCF₃, —CN, -halogen,—C₁-C₄-alkyl, ═O, and —SO₂—C₁-C₄-alkyl, or wherein Z is C,

and R₄ denotes —H and R₅ is selected from a group of the structure-L₁-R₁₈,

wherein L₁ is selected from among —NH—, —N(C₁-C₄-alkyl)-,

wherein R₁₈ is selected from among —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl,—C₃-C₈-cycloalkyl, and —C₃-C₈-heterocyclyl,

wherein R₁₈ is optionally substituted by one or more groups selectedfrom among halogen, —CF₃, —OCF₃, —CN, —OH, —O—C₁-C₄-alkyl, —C₁-C₆-alkyl,—NH—C(O)—C₁-C₆-alkyl, —N(C₁-C₄-alkyl)-C(O)—C₁-C₆-alkyl,—C(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl, —NH—S(O)₂—C₁-C₆-alkyl,—N(C₁-C₄-alkyl)-S(O)₂—C₁-C₆-alkyl, and —C(O)—O—C₁-C₆-alkyl,

and wherein R₄, R₅ and R₁₈ are optionally further substituted byspiro-C₃-C₈-cycloalkyl or spiro-C₃-C₈-heterocyclyl such that togetherwith R₄, R₅ and/or R₁₈ a spirocycle is formed, wherein saidspiro-C₃-C₈-heterocyclyl optionally comprises one or more groupsselected from among nitrogen, —C(O)—, —SO₂—, and —N(SO₂—C₁-C₄-alkyl)- inthe ring,

or wherein R₄, R₅ and R₁₈ are optionally further bi-valently substitutedby one or more spirocyclic or annellated ring forming groups selectedfrom among —C₁-C₆-alkylene, —C₂-C₆-alkenylene, and —C₄-C₆-alkynylene, inwhich one or two carbon centers may optionally be replaced by one or twohetero atoms selected from among N, O and S and which may optionally besubstituted by one or more groups on one ring atom or on twoneighbouring ring atoms selected from among —OH, —NH₂, —C₁-C₃-alkyl,—O—C₁-C₆-alkyl, —CN, —CF₃, —OCF₃, and halogen.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₁₉, R₁₉′, E, G, Q, and n as hereinbefore or below defined, wherein

Z is N, and R₄ denotes an electron pair, and R₅ is a group selected fromamong —H, —C₁-C₆-alkyl, —NH₂, —C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl,—C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl, and —C(O)—N(R₈,R₈′), with R₈ and R₈′independently being selected from among —H, and —C₁-C₆-alkyl,

and wherein R₅ if different from an —H is optionally substituted withone or more groups selected from among -halogen, —OH, —CF₃, —CN,—C₁-C₆-alkyl, —O—C₁-C₆-alkyl, —O—C₃-C₈-cycloalkyl,—O—C₃-C₈-heterocyclyl, —O—C₅-C₁₀-aryl, —O—C₅-C₁₀-heteroaryl,—C₀-C₆-alkylene-CN, —C₀-C₄-alkylene-O—C₁-C₄-alkyl,—C₀-C₄-alkylene-O—C₃-C₈-cycloalkyl,—C₀-C₄-alkylene-O—C₃-C₈-heterocyclyl, —C₀-C₄-alkylene-O—C₅-C₁₀-aryl,—C₀-C₄-alkylene-O—C₅-C₁₀-heteroaryl,—C₀-C₄-alkylene-Q-C₀-C₄-alkyl-N(R₉,R₉′),—C₀-C₄-alkylene-N(R₁₀)-Q-C₁-C₄-alkyl,—C₀-C₄-alkylene-N(R₁₀)-Q-C₃-C₈-cycloalkyl,

—C₀-C₄-alkylene-N(R₁₀)-Q-C₃-C₈-heterocyclyl,—C₀-C₄-alkylene-N(R₁₀)-Q-C₅-C₁₀-aryl,—C₀-C₄-alkylene-N(R₁₀)-Q-C₅-C₁₀-heteroaryl,—C₀-C₄-alkylene-Q-N(R₁₁,R₁₁′), —C₀-C₄-alkylene-N(R₁₂)-Q-N(R₁₃,R₁₃′),—C₀-C₄-alkylene-R₁₄, —C₀-C₄-alkylene-Q-C₁-C₆-alkyl,—C₀-C₄-alkylene-Q-C₃-C₈-cycloalkyl,—C₀-C₄-alkylene-Q-C₃-C₈-heterocyclyl, —C₀-C₄-alkylene-Q-C₅-C₁₀-aryl,—C₀-C₄-alkylene-Q-C₅-C₁₀-heteroaryl, —C₀-C₄-alkylene-O-Q-N(R₁₅,R₁₅′),and —C₀-C₄-alkylene-N(R₁₆)-Q-O—(R₁₇),

wherein Q is selected from among —C(O)—, and —SO₂—,

wherein R₁₀, R₁₂, R₁₆, are independently selected from among —H,—C₁-C₆-alkyl, and —C₃-C₆-cycloalkyl,

wherein R₉, R₉′, R₁₁, R₁₁′, R₁₃, R₁₃′, R₁₅, R₁₅′, are independentlyselected from among —H, —C₁-C₆-alkyl, and —C₃-C₆-cycloalkyl,

or wherein R₉ and R₉′, R₁₁ and R₁₁′, R₁₃ and R₁₃′, R₁₅ and R₁₅′ togetherform a —C₂-C₆-alkylene group,

wherein R₁₄ and R₁₇ are independently selected from among —H,—C₁-C₆-alkyl, —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl, —C₃-C₈-cycloalkyl, and—C₃-C₈-heterocyclyl, wherein said —C₃-C₈-heterocyclyl optionallycomprises nitrogen and/or —SO₂— in the ring,

and wherein R₁₄ and R₁₇ are optionally substituted with one or moregroups selected from among —OH, —OCH₃, —CF₃, —OCF₃, —CN, -halogen,—C₁-C₄-alkyl, ═O, and —SO₂—C₁-C₄-alkyl.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, E, G, Q, and n as herein before orbelow defined,

wherein Z is C,

and R₄ and R₅ are independently selected from among —H, -i-propyl,-amino, -pyrrolidinyl, -piperidinyl, -morpholinyl, -azepanyl,-oxazepanyl, -piperazinyl, -azetidinyl, -tetrahydropyranyl,-cyclopentyl, -cyclohexyl, and —C(O)—N(R₈,R₈′), with R₈ and R₈′independently being selected from among —H and —C₁-C₆-alkyl,

wherein R₄ and R₅ if different from —H are optionally independentlysubstituted with one or more groups selected from among -fluoro,-methyl, -ethyl, propyl, -i-propyl, -butyl, -i-butyl, -t-butyl,-hydroxy, —CF₃, —OCF₃, —CN, —O—CH₃, —O—C₂H₅, —O—C₃H₇, —CH₂—CN,—CH₂—O—CH₃, —(CH₂)₂—O—CH₃, —C(O)—CH₃, —C(O)—C₂H₅, —C(O)—C₃H₇, —COOH,—C(O)—NH₂, —C(O)—NH—CH₃, —C(O)—N(CH₃)₂, —NH—C(O)—CH₃, —N(CH₃)C(O)—CH₃,—NH—C(O)—C₂H₅, —N(CH₃)—C(O)—C₂H₅, —NH—C(O)—C₃H₇, —N(CH₃)—C(O)—C₃H₇,—NH—SO₂—CH₃, —N(CH₃)—SO₂—CH₃, —N(C₂H₅)—SO₂—CH₃, —N(C₃H₇)—SO₂—CH₃,—NH—SO₂—C₂H₅, —N(CH₃)—SO₂—C₂H₅, —N(C₂H₅)—SO₂—C₂H₅, —N(C₃H₇)—SO₂—C₂H₅,—NH—SO₂—C₃H₇, —N(CH₃)—SO₂—C₃H₇, —N(C₂H₅)—SO₂—C₃H₇, —N(C₃H₇)—SO₂—C₃H₇,—NH—SO₂—C₃H₅, —N(CH₃)—SO₂—C₃H₅, —N(C₂H₅)—SO₂—C₃H₅, —N(C₃H₇)—SO₂—C₂H₅,—CH₂—NH—SO₂—CH₃, —CH₂—N(CH₃)—SO₂—CH₃, —CH₂—NH—SO₂—C₂H₅,—CH₂—N(CH₃)—SO₂—C₂H₅, —CH₂—NH—SO₂—C₃H₇, —CH₂—N(CH₃)—SO₂—C₃H₇,—CH₂—NH—SO₂—C₃H₅, —CH₂—N(CH₃)—SO₂—C₃H₅, —NH—C(O)—NH₂, —N(CH₃)—C(O)—NH₂,—NH—C(O)—NH—CH₃, —N(CH₃)—C(O)—NH—CH₃, —NH—C(O)—N(CH₃)₂,—N(CH₃)—C(O)—N(CH₃)₂, —SO₂—NH₂, —SO₂—NH(CH₃), —SO₂—N(CH₃)₂,—C(O)—NH—C₂H₅, —C(O)—N(CH₃)—C₂H₅, —C(O)—N(CH₃)—C₃H₇, —C(O)—N(CH₃)—C₄H₉,—C(O)—NH—CH(CH₃)—C₂H₅, —C(O)—N(CH₃)—CH(CH₃)—C₂H₅, —CH₂—C(O)—NH₂,—CH₂—C(O)—NH—CH₃, —CH₂—C(O)—N(CH₃)₂, —N(CH₃)—SO₂—N(CH₃)₂,—(C₆-aryl)-COOH, -phenyl, -pyridin-4-yl, —CH₂-3-methyl-oxetan-3-yl,—O-1,2-difluoro-phen-5-yl, —O-pyridin-2-yl, -pyrrolidine-2-one-1-yl,-3,5-dimethyl-[1,2,4]triazol-4-yl, 3-methyl-[1,2,4]oxadiazol-5-yl,

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, E, G, Q, and n as herein before orbelow defined,

wherein Z is N,

and R₄ denotes an electron pair, and R₅ is a group selected from among—H, -i-propyl, -amino, -pyrrolidinyl, -piperidinyl, -morpholinyl,-azepanyl, -oxazepanyl, -piperazinyl, -azetidinyl, -tetrahydropyranyl,-cyclopentyl, -cyclohexyl, and —C(O)—N(R₈,R₈′), with R₈ and R₈′independently being selected from among —H and —C₁-C₆-alkyl,

wherein R₅ if different from —H is optionally substituted with one ormore groups selected from among -fluoro, -methyl, -ethyl, propyl,-i-propyl, -butyl, -i-butyl, -t-butyl, -hydroxy, —CF₃, —OCF₃, —CN,—O—CH₃, —O—C₂H₅, —O—C₃H₇, —CH₂—CN, —CH₂—O—CH₃, —(CH₂)₂—O—CH₃, —C(O)—CH₃,—C(O)—C₂H₅, —C(O)—C₃H₇, —COOH, —C(O)—NH₂, —C(O)—NH—CH₃, —C(O)—N(CH₃)₂,—NH—C(O)—CH₃, —N(CH₃)C(O)—CH₃, —NH—C(O)—C₂H₅, —N(CH₃)—C(O)—C₂H₅,—NH—C(O)—C₃H₇, —N(CH₃)—C(O)—C₃H₇, —NH—SO₂—CH₃, —N(CH₃)—SO₂—CH₃,—N(C₂H₅)—SO₂—CH₃, —N(C₃H₇)—SO₂—CH₃, —NH—SO₂—C₂H₅, —N(CH₃)—SO₂—C₂H₅,—N(C₂H₅)—SO₂—C₂H₅, —N(C₃H₇)—SO₂—C₂H₅, —NH—SO₂—C₃H₇, —N(CH₃)—SO₂—C₃H₇,—N(C₂H₅)—SO₂—C₃H₇, —N(C₃H₇)—SO₂—C₃H₇, —NH—SO₂—C₃H₅, —N(CH₃)—SO₂—C₃H₅,—N(C₂H₅)—SO₂—C₃H₅, —N(C₃H₇)—SO₂—C₂H₅, —CH₂—NH—SO₂—CH₃,—CH₂—N(CH₃)—SO₂—CH₃, —CH₂—NH—SO₂—C₂H₅, —CH₂—N(CH₃)—SO₂—C₂H₅,—CH₂—NH—SO₂—C₃H₇, —CH₂—N(CH₃)—SO₂—C₃H₇, —CH₂—NH—SO₂—C₃H₅,—CH₂—N(CH₃)—SO₂—C₃H₅, —NH—C(O)—NH₂, —N(CH₃)—C(O)—NH₂, —NH—C(O)—NH—CH₃,—N(CH₃)—C(O)—NH—CH₃, —NH—C(O)—N(CH₃)₂, —N(CH₃)—C(O)—N(CH₃)₂, —SO₂—NH₂,—SO₂—NH(CH₃), —SO₂—N(CH₃)₂, —C(O)—NH—C₂H₅, —C(O)—N(CH₃)—C₂H₅,—C(O)—N(CH₃)—C₃H₇, —C(O)—N(CH₃)—C₄H₉, —C(O)—NH—CH(CH₃)—C₂H₅,—C(O)—N(CH₃)—CH(CH₃)—C₂H₅, —CH₂—C(O)—NH₂, —CH₂—C(O)—NH—CH₃,—CH₂—C(O)—N(CH₃)₂, —N(CH₃)—SO₂—N(CH₃)₂, —(C₆-aryl)-COOH, -phenyl,-pyridin-4-yl, —CH₂-3-methyl-oxetan-3-yl, —O-1,2-difluoro-phen-5-yl,—O-pyridin-2-yl, -pyrrolidine-2-one-1-yl,-3,5-dimethyl-[1,2,4]triazol-4-yl, 3-methyl-[1,2,4]oxadiazol-5-yl,

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′ R₁₂,R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, L₁, E, G, Q, and nas herein before or below defined,

wherein Z is C,

and R₄ and R₅ are independently selected from among —H, -i-propyl,-amino, -pyrrolidinyl, -piperidinyl, -morpholinyl, -azepanyl,-oxazepanyl, -piperazinyl, -azetidinyl, -tetrahydropyranyl,-cyclopentyl, -cyclohexyl, and —C(O)—N(R₈,R₈′), with R₈ and R₈′independently being selected from among —H and —C₁-C₆-alkyl,

wherein R₄ and R₅ if different from —H are optionally independentlysubstituted with one or more groups selected from among -fluoro,-methyl, -ethyl, propyl, -i-propyl, -butyl, -i-butyl, -t-butyl,-hydroxy, —CF₃, —OCF₃, —CN, —O—CH₃, —O—C₂H₅, —O—C₃H₇, —CH₂—CN,—CH₂—O—CH₃, —(CH₂)₂—O—CH₃, —C(O)—CH₃, —C(O)—C₂H₅, —C(O)—C₃H₇, —COOH,—C(O)—NH₂, —C(O)—NH—CH₃, —C(O)—N(CH₃)₂, —NH—C(O)—CH₃, —N(CH₃)C(O)—CH₃,—NH—C(O)—C₂H₅, —N(CH₃)—C(O)—C₂H₅, —NH—C(O)—C₃H₇, —N(CH₃)—C(O)—C₃H₇,—NH—SO₂—CH₃, —N(CH₃)—SO₂—CH₃, —N(C₂H₅)—SO₂—CH₃, —N(C₃H₇)—SO₂—CH₃,—NH—SO₂—C₂H₅, —N(CH₃)—SO₂—C₂H₅, —N(C₂H₅)—SO₂—C₂H₅, —N(C₃H₇)—SO₂—C₂H₅,—NH—SO₂—C₃H₇, —N(CH₃)—SO₂—C₃H₇, —N(C₂H₅)—SO₂—C₃H₇, —N(C₃H₇)—SO₂—C₃H₇,—NH—SO₂—C₃H₅, —N(CH₃)—SO₂—C₃H₅, —N(C₂H₅)—SO₂—C₃H₅, —N(C₃H₇)—SO₂—C₂H₅,—CH₂—NH—SO₂—CH₃, —CH₂—N(CH₃)—SO₂—CH₃, —CH₂—NH—SO₂—C₂H₅,—CH₂—N(CH₃)—SO₂—C₂H₅, —CH₂—NH—SO₂—C₃H₇, —CH₂—N(CH₃)—SO₂—C₃H₇,—CH₂—NH—SO₂—C₃H₅, —CH₂—N(CH₃)—SO₂—C₃H₅, —NH—C(O)—NH₂, —N(CH₃)—C(O)—NH₂,—NH—C(O)—NH—CH₃, —N(CH₃)—C(O)—NH—CH₃, —NH—C(O)—N(CH₃)₂,—N(CH₃)—C(O)—N(CH₃)₂, —SO₂—NH₂, —SO₂—NH(CH₃), —SO₂—N(CH₃)₂,—C(O)—NH—C₂H₅, —C(O)—N(CH₃)—C₂H₅, —C(O)—N(CH₃)—C₃H₇, —C(O)—N(CH₃)—C₄H₉,—C(O)—NH—CH(CH₃)—C₂H₅, —C(O)—N(CH₃)—CH(CH₃)—C₂H₅, —CH₂—C(O)—NH₂,—CH₂—C(O)—NH—CH₃, —CH₂—C(O)—N(CH₃)₂, —N(CH₃)—SO₂—N(CH₃)₂, -phenyl,-pyridin-4-yl, —CH₂-3-methyl-oxetan-3-yl, —O-1,2-difluoro-phen-5-yl,—O-pyridin-2-yl, -pyrrolidine-2-one-1-yl,-3,5-dimethyl-[1,2,4]triazol-4-yl, 3-methyl-[1,2,4]oxadiazol-5-yl,

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′ R₁₂,R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, L₁, E, G, Q, and nas herein before or below defined,

wherein Z is N,

and R₄ denotes an electron pair, and R₅ is a group selected from among—H, -i-propyl, -amino, -pyrrolidinyl, -piperidinyl, -morpholinyl,-azepanyl, -oxazepanyl, -piperazinyl, -azetidinyl, -tetrahydropyranyl,-cyclopentyl, -cyclohexyl, and —C(O)—N(R₈,R₈′), with R₈ and R₈′independently being selected from among —H and —C₁-C₆-alkyl,

wherein R₅ if different from an —H is optionally substituted with one ormore groups selected from among -fluoro, -methyl, -ethyl, propyl,-i-propyl, -butyl, -i-butyl, -t-butyl, -hydroxy, —CF₃, —OCF₃, —CN,—O—CH₃, —O—C₂H₅, —O—C₃H₇, —CH₂—CN, —CH₂—O—CH₃, —(CH₂)₂—O—CH₃, —C(O)—CH₃,—C(O)—C₂H₅, —C(O)—C₃H₇, —COOH, —C(O)—NH₂, —C(O)—NH—CH₃, —C(O)—N(CH₃)₂,—NH—C(O)—CH₃, —N(CH₃)C(O)—CH₃, —NH—C(O)—C₂H₅, —N(CH₃)—C(O)—C₂H₅,—NH—C(O)—C₃H₇, —N(CH₃)—C(O)—C₃H₇, —NH—SO₂—CH₃, —N(CH₃)—SO₂—CH₃,—N(C₂H₅)—SO₂—CH₃, —N(C₃H₇)—SO₂—CH₃, —NH—SO₂—C₂H₅, —N(CH₃)—SO₂—C₂H₅,—N(C₂H₅)—SO₂—C₂H₅, —N(C₃H₇)—SO₂—C₂H₅, —NH—SO₂—C₃H₇, —N(CH₃)—SO₂—C₃H₇,—N(C₂H₅)—SO₂—C₃H₇, —N(C₃H₇)—SO₂—C₃H₇, —NH—SO₂—C₃H₅, —N(CH₃)—SO₂—C₃H₅,—N(C₂H₅)—SO₂—C₃H₅, —N(C₃H₇)—SO₂—C₂H₅, —CH₂—NH—SO₂—CH₃,—CH₂—N(CH₃)—SO₂—CH₃, —CH₂—NH—SO₂—C₂H₅, —CH₂—N(CH₃)—SO₂—C₂H₅,—CH₂—NH—SO₂—C₃H₇, —CH₂—N(CH₃)—SO₂—C₃H₇, —CH₂—NH—SO₂—C₃H₅,—CH₂—N(CH₃)—SO₂—C₃H₅, —NH—C(O)—NH₂, —N(CH₃)—C(O)—NH₂, —NH—C(O)—NH—CH₃,—N(CH₃)—C(O)—NH—CH₃, —NH—C(O)—N(CH₃)₂, —N(CH₃)—C(O)—N(CH₃)₂, —SO₂—NH₂,—SO₂—NH(CH₃), —SO₂—N(CH₃)₂, —C(O)—NH—C₂H₅, —C(O)—N(CH₃)—C₂H₅,—C(O)—N(CH₃)—C₃H₇, —C(O)—N(CH₃)—C₄H₉, —C(O)—NH—CH(CH₃)—C₂H₅,—C(O)—N(CH₃)—CH(CH₃)—C₂H₅, —CH₂—C(O)—NH₂, —CH₂—C(O)—NH—CH₃,—CH₂—C(O)—N(CH₃)₂, —N(CH₃)—SO₂—N(CH₃)₂, -phenyl, -pyridin-4-yl,—CH₂-3-methyl-oxetan-3-yl, —O-1,2-difluoro-phen-5-yl, —O-pyridin-2-yl,-pyrrolidine-2-one-1-yl, -3,5-dimethyl-[1,2,4]triazol-4-yl,3-methyl-[1,2,4]oxadiazol-5-yl,

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′ R₁₂,R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀, R₂₀′, L₁, E,G, Q, and n as herein before or below defined,

wherein Z is C,

and R₄ denotes —H and R₅ is a group selected from among, -i-propyl,-amino, -pyrrolidinyl, -piperidinyl, -morpholinyl, -azepanyl,-oxazepanyl, -piperazinyl, -azetidinyl, -tetrahydropyranyl,-cyclopentyl, -cyclohexyl, and —C(O)—N(R₈,R₈′), with R₈ and R₈′independently being selected from among —H and —C₁-C₆-alkyl,

wherein R₅ is optionally substituted with one or more groups selectedfrom among -fluoro, -methyl, -ethyl, propyl, -i-propyl, -butyl,-i-butyl, -t-butyl, -hydroxy, —CF₃, —OCF₃, —CN, —O—CH₃, —O—C₂H₅,—O—C₃H₇, —CH₂—CN, —CH₂—O—CH₃, —(CH₂)₂—O—CH₃, —C(O)—CH₃, —C(O)—C₂H₅,—C(O)—C₃H₇, —COOH, —C(O)—NH₂, —C(O)—NH—CH₃, —C(O)—N(CH₃)₂, —NH—C(O)—CH₃,—N(CH₃)C(O)—CH₃, —NH—C(O)—C₂H₅, —N(CH₃)—C(O)—C₂H₅, —NH—C(O)—C₃H₇,—N(CH₃)—C(O)—C₃H₇, —NH—SO₂—CH₃, —N(CH₃)—SO₂—CH₃, —N(C₂H₅)—SO₂—CH₃,—N(C₃H₇)—SO₂—CH₃, —NH—SO₂—C₂H₅, —N(CH₃)—SO₂—C₂H₅, —N(C₂H₅)—SO₂—C₂H₅,—N(C₃H₇)—SO₂—C₂H₅, —NH—SO₂—C₃H₇, —N(CH₃)—SO₂—C₃H₇, —N(C₂H₅)—SO₂—C₃H₇,—N(C₃H₇)—SO₂—C₃H₇, —NH—SO₂—C₃H₅, —N(CH₃)—SO₂—C₃H₅, —N(C₂H₅)—SO₂—C₃H₅,—N(C₃H₇)—SO₂—C₂H₅, —CH₂—NH—SO₂—CH₃, —CH₂—N(CH₃)—SO₂—CH₃,—CH₂—NH—SO₂—C₂H₅, —CH₂—N(CH₃)—SO₂—C₂H₅, —CH₂—NH—SO₂—C₃H₇,—CH₂—N(CH₃)—SO₂—C₃H₇, —CH₂—NH—SO₂—C₃H₅, —CH₂—N(CH₃)—SO₂—C₃H₅,—NH—C(O)—NH₂, —N(CH₃)—C(O)—NH₂, —NH—C(O)—NH—CH₃, —N(CH₃)—C(O)—NH—CH₃,—NH—C(O)—N(CH₃)₂, —N(CH₃)—C(O)—N(CH₃)₂, —SO₂—NH₂, —SO₂—NH(CH₃),—SO₂—N(CH₃)₂, —C(O)—NH—C₂H₅, —C(O)—N(CH₃)—C₂H₅, —C(O)—N(CH₃)—C₃H₇,—C(O)—N(CH₃)—C₄H₉, —C(O)—NH—CH(CH₃)—C₂H₅, —C(O)—N(CH₃)—CH(CH₃)—C₂H₅,—CH₂—C(O)—NH₂, —CH₂—C(O)—NH—CH₃, —CH₂—C(O)—N(CH₃)₂, —N(CH₃)—SO₂—N(CH₃)₂,-phenyl, -pyridin-4-yl, —CH₂-3-methyl-oxetan-3-yl,—O-1,2-difluoro-phen-5-yl, —O-pyridin-2-yl, -pyrrolidine-2-one-1-yl,-3,5-dimethyl-[1,2,4]triazol-4-yl, 3-methyl-[1,2,4]oxadiazol-5-yl,

or wherein R₅ is optionally substituted with one or more groups selectedfrom among —(C₆-aryl)-COOH,

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′ R₁₂,R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀, R₂₀′, L₁, E,G, Q, and n as herein before or below defined,

wherein Z is C,

and R₄ and R₅ are independently selected from among —H, -i-propyl,-amino, -pyrrolidinyl, -piperidinyl, -morpholinyl, -azepanyl,-oxazepanyl, -piperazinyl, -azetidinyl, -tetrahydropyranyl,-cyclopentyl, -cyclohexyl, and —C(O)—N(R₈,R₈′), with R₈ and R₈′independently being selected from among —H and —C₁-C₆-alkyl,

wherein R₄ and R₅ if different from —H are optionally independentlysubstituted with one or more groups selected from among -fluoro,-methyl, -ethyl, propyl, -i-propyl, -butyl, -i-butyl, -t-butyl,-hydroxy, —CF₃, —CN, —CH₂—CN, —CH₂—O—CH₃, —(CH₂)₂—O—CH₃, —C(O)—CH₃,—C(O)—C₂H₅, —C(O)—C₃H₇, —COOH, —C(O)—NH₂, —C(O)—NH—CH₃, —C(O)—N(CH₃)₂,—NH—C(O)—CH₃, —N(CH₃)C(O)—CH₃, —NH—C(O)—C₂H₅, —N(CH₃)—C(O)—C₂H₅,—NH—C(O)—C₃H₇, —N(CH₃)—C(O)—C₃H₇, —NH—SO₂—CH₃, —N(CH₃)—SO₂—CH₃,—N(C₂H₅)—SO₂—CH₃, —N(C₃H₇)—SO₂—CH₃, —NH—SO₂—C₂H₅, —N(CH₃)—SO₂—C₂H₅,—N(C₂H₅)—SO₂—C₂H₅, —N(C₃H₇)—SO₂—C₂H₅, —NH—SO₂—C₃H₇, —N(CH₃)—SO₂—C₃H₇,—N(C₂H₅)—SO₂—C₃H₇, —N(C₃H₇)—SO₂—C₃H₇, —NH—SO₂—C₃H₅, —N(CH₃)—SO₂—C₃H₅,—N(C₂H₅)—SO₂—C₃H₅, —N(C₃H₇)—SO₂—C₂H₅, —CH₂—NH—SO₂—CH₃,—CH₂—N(CH₃)—SO₂—CH₃, —CH₂—NH—SO₂—C₂H₅, —CH₂—N(CH₃)—SO₂—C₂H₅,—CH₂—NH—SO₂—C₃H₇, —CH₂—N(CH₃)—SO₂—C₃H₇, —CH₂—NH—SO₂—C₃H₅,—CH₂—N(CH₃)—SO₂—C₃H₅, —NH—C(O)—NH₂, —N(CH₃)—C(O)—NH₂, —NH—C(O)—NH—CH₃,—N(CH₃)—C(O)—NH—CH₃, —NH—C(O)—N(CH₃)₂, —N(CH₃)—C(O)—N(CH₃)₂, —SO₂—NH₂,—SO₂—NH(CH₃), —SO₂—N(CH₃)₂, —C(O)—NH—C₂H₅, —C(O)—N(CH₃)—C₂H₅,—C(O)—N(CH₃)—C₃H₇, —C(O)—N(CH₃)—C₄H₉, —C(O)—NH—CH(CH₃)—C₂H₅,—C(O)—N(CH₃)—CH(CH₃)—C₂H₅, —CH₂—C(O)—NH₂, —CH₂—C(O)—NH—CH₃,—CH₂—C(O)—N(CH₃)₂, —N(CH₃)—SO₂—N(CH₃)₂, -phenyl, -pyridin-4-yl,—CH₂-3-methyl-oxetan-3-yl, -pyrrolidine-2-one-1-yl,-3,5-dimethyl-[1,2,4]triazol-4-yl, 3-methyl-[1,2,4]oxadiazol-5-yl,

or wherein R₄ and R₅ if different from —H are optionally independentlysubstituted with one or more groups selected from among —(C₆-aryl)-COOH,

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, E, G, Q, and n as herein before orbelow defined,

wherein Z is C,

and R₄ and R₅ are independently selected from among —H, -i-propyl,-amino, -pyrrolidinyl, -piperidinyl, -morpholinyl, -azepanyl,-oxazepanyl, -piperazinyl, -azetidinyl, -tetrahydropyranyl,-cyclopentyl, -cyclohexyl, and —C(O)—N(R₈,R₈′), with R₈ and R₈′independently being selected from among —H and —C₁-C₆-alkyl,

wherein R₄ and R₅ if different from —H are optionally independentlysubstituted with one or more groups selected from among -fluoro,-methyl, -ethyl, propyl, -i-propyl, -butyl, -i-butyl, -t-butyl,-hydroxy, —CF₃, —CN, —CH₂—CN, —CH₂—O—CH₃, —(CH₂)₂—O—CH₃, —C(O)—CH₃,—C(O)—C₂H₅, —C(O)—C₃H₇, —COOH, —C(O)—NH₂, —C(O)—NH—CH₃, —C(O)—N(CH₃)₂,—CH₂—NH—SO₂—CH₃, —CH₂—N(CH₃)—SO₂—CH₃, —CH₂—NH—SO₂—C₂H₅,—CH₂—N(CH₃)—SO₂—C₂H₅, —CH₂—NH—SO₂—C₃H₇, —CH₂—N(CH₃)—SO₂—C₃H₇,—CH₂—NH—SO₂—C₃H₅, —CH₂—N(CH₃)—SO₂—C₃H₅, —C(O)—NH—C₂H₅,—C(O)—N(CH₃)—C₂H₅, —C(O)—N(CH₃)—C₃H₇, —C(O)—N(CH₃)—C₄H₉,—C(O)—NH—CH(CH₃)—C₂H₅, —C(O)—N(CH₃)—CH(CH₃)—C₂H₅, —CH₂—C(O)—NH₂,—CH₂—C(O)—NH—CH₃, —CH₂—C(O)—N(CH₃)₂, —N(CH₃)—SO₂—N(CH₃)₂,—(C₆-aryl)-COOH, -phenyl, -pyridin-4-yl, —CH₂-3-methyl-oxetan-3-yl,-pyrrolidine-2-one-1-yl, -3,5-dimethyl-[1,2,4]triazol-4-yl,3-methyl-[1,2,4]oxadiazol-5-yl,

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′ R₁₂,R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, L₁, E, G, Q, and nas herein before or below defined,

wherein Z is C,

and R₄ and R₅ are independently selected from among —H, -i-propyl,-amino, -pyrrolidinyl, -piperidinyl, -morpholinyl, -azepanyl,-oxazepanyl, -piperazinyl, -azetidinyl, -tetrahydropyranyl,-cyclopentyl, -cyclohexyl, and —C(O)—N(R₈,R₈′), with R₈ and R₈′independently being selected from among —H and —C₁-C₆-alkyl,

wherein R₄ and R₅ if different from -H are optionally independentlysubstituted with one or more groups selected from among -fluoro,-methyl, -ethyl, propyl, -i-propyl, -butyl, -i-butyl, -t-butyl,-hydroxy, —CF₃, —CN, —CH₂—CN, —CH₂—O—CH₃, —(CH₂)₂—O—CH₃, —C(O)—CH₃,—C(O)—C₂H₅, —C(O)—C₃H₇, —COOH, —C(O)—NH₂, —C(O)—NH—CH₃, —C(O)—N(CH₃)₂,—CH₂—NH—SO₂—CH₃, —CH₂—N(CH₃)—SO₂—CH₃, —CH₂—NH—SO₂—C₂H₅,—CH₂—N(CH₃)—SO₂—C₂H₅, —CH₂—NH—SO₂—C₃H₇, —CH₂—N(CH₃)—SO₂—C₃H₇,—CH₂—NH—SO₂—C₃H₅, —CH₂—N(CH₃)—SO₂—C₃H₅, —C(O)—NH—C₂H₅,—C(O)—N(CH₃)—C₂H₅, —C(O)—N(CH₃)—C₃H₇, —C(O)—N(CH₃)—C₄H₉,—C(O)—NH—CH(CH₃)—C₂H₅, —C(O)—N(CH₃)—CH(CH₃)—C₂H₅, —CH₂—C(O)—NH₂,—CH₂—C(O)—NH—CH₃, —CH₂—C(O)—N(CH₃)₂, —N(CH₃)—SO₂—N(CH₃)₂, -phenyl,-pyridin-4-yl, —CH₂-3-methyl-oxetan-3-yl, -pyrrolidine-2-one-1-yl,-3,5-dimethyl-[1,2,4]triazol-4-yl, 3-methyl-[1,2,4]oxadiazol-5-yl,

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, E, G, Q, and n as herein before orbelow defined,

wherein Z is C,

and R₄ denotes —H and R₅ is a group of the structure -L₁-R₁₈,

wherein L₁ is selected from among —NH—, —N(CH₃)—, —N(C₂H₅)—, and a bond

and wherein R₁₈ is selected from among -tetrahydropyranyl, -cyclopropyl,-cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl,-pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -chromanyl,-octahydro-pyrano-pyrrolyl, -octahydro-pyrano-pyridinyl,-octahydro-pyrano-oxazinyl, -oxaspirodecanyl, and-tetrahydro-naphthyridinyl, wherein R₁₈ is optionally substituted by oneor more groups selected from among —F, —CF₃, —OCF₃, —CN, —OH, —O—CH₃,—CH₃, —NH—C(O)—CH₃, —N(CH₃)—C(O)—CH₃, —C(O)—CH₃, —S(O)₂—CH₃,—NH—S(O)₂—CH₃, —N(CH₃)—S(O)₂—CH₃, —N(CH₃)—S(O)₂—CH₂—CH₃, and—C(O)—O—C₂H₅, more preferred wherein R₁₈ is optionally substituted byone or more groups selected from among —F, —O—CH₃, —N(CH₃)—S(O)₂—CH₃,most preferred wherein R₁₈ is optionally substituted by —O—CH₃.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁,R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀,R₂₀′, L₁, E, G, Z, Q, and n as herein before or below defined, whereinR₁₈ is optionally substituted by one or more groups selected from among—F, and —O—CH₃,

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, E, G, Q, and n as herein before orbelow defined,

wherein Z is C,

and R₄ denotes —H and R₅ is a group of the structure -L₁-R₁₈,

wherein L₁ is selected from among —NH—, —N(CH₃)—, —N(C₂H₅)—, and a bond

and wherein R₁₈ is selected from among -tetrahydropyranyl, -cyclopropyl,-cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl,-pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -chromanyl,-octahydro-pyrano-pyrrolyl, -octahydro-pyrano-pyridinyl,-octahydro-pyrano-oxazinyl, -oxaspirodecanyl, and-tetrahydro-naphthyridinyl, wherein R₁₈ is optionally substituted by —F.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′ R₁₂,R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₉, R₁₉′, E, G, Q, and n as hereinbefore or below defined,

wherein Z is C,

and R₄ denotes —H and R₅ is a group of the structure -L₁-R₁₈,

wherein L₁ is selected from among —NH—, —N(CH₃)—, and —N(C₂H₅)—,

and wherein R₁₈ is selected from among -tetrahydropyranyl, -cyclopropyl,-cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl,-pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -chromanyl,-octahydro-pyrano-pyrrolyl, -octahydro-pyrano-pyridinyl,-octahydro-pyrano-oxazinyl, -oxaspirodecanyl, and-tetrahydro-naphthyridinyl, wherein R₁₈ is optionally substituted by oneor more groups selected from among —F, —CF₃, —OCF₃, —CN, —OH, —O—CH₃,—CH₃, —NH—C(O)—CH₃, —N(CH₃)—C(O)—CH₃, —C(O)—CH₃, —S(O)₂—CH₃,—NH—S(O)₂—CH₃, —N(CH₃)—S(O)₂—CH₃, —N(CH₃)—S(O)₂—CH₂—CH₃, and—C(O)—O—C₂H₅.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, E, G, Q, and n as herein before orbelow defined,

wherein Z is C,

and R₄ denotes —H and R₅ is a group of the structure -L₁-R₁₈,

wherein L₁ is selected from among —NH—, —N(CH₃)—, —N(C₂H₅)—, and a bond,

and wherein R₄, R₅ and R₁₈ are optionally further bi-valentlysubstituted by one or more groups selected from among

on one ring atom or on two neighboring ring atoms, such that spirocyclicor annellated rings are formed.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′ R₁₂,R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₉, R₁₉′, E, G, Q, and n as hereinbefore or below defined,

wherein Z is C,

and R₄ denotes —H and R₅ is a group of the structure -L₁-R₁₈,

wherein L₁ is selected from among —NH—, —N(CH₃)—, and —N(C₂H₅)—,

and wherein R₄, R₅ and R₁₈ are optionally further bi-valentlysubstituted by one or more groups selected from among

on one ring atom or on two neighboring ring atoms, such that spirocyclicor annellated rings are formed.

Preferred compounds of formula (I) according to the invention arecompounds with R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀, R₂₀′, L₁,E, G, Z, Q, and n as herein before or below defined,

wherein R₁ is a group selected from among —H, -halogen, —CN,—C₁-C₃-alkyl, —CH═CH₂, —C≡CH, and —CF₃, more preferred wherein R₁ is agroup selected from among —H, -halogen, and -methyl.

Preferred compounds of formula (I) according to the invention arecompounds with R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, L₁, E, G, Z,Q, and n as herein before or below defined,

wherein R₁ is a group selected from among —H, -halogen, —CN,—C₁-C₃-alkyl, —CH═CH₂, —C≡CH, and —CF₃, more preferred wherein R₁ is agroup selected from among —H, -halogen, and -methyl.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀, R₂₀′, L₁,E, G, Z, Q, and n as herein before or below defined,

wherein R₇ is selected from among —C₅-C₆-aryl, —C₅-C₆-heteroaryl,—C₃-C₈-cycloalkyl, and —C₃-C₈-heterocyclyl,

and wherein the ring R₇ is optionally substituted with one or moregroups selected from among —CF₃, —O—CF₃, —S—CF₃, —CN, -methyl,—C(CH₃)₂—CN, and -halogen.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, L₁, E, G, Z,Q, and n as herein before or below defined,

wherein R₇ is selected from among —C₅-C₆-aryl, —C₅-C₆-heteroaryl,—C₃-C₈-cycloalkyl, and —C₃-C₈-heterocyclyl,

and wherein the ring R₇ is optionally substituted with one or moregroups selected from among —CF₃, —O—CF₃, —CN, -methyl, —C(CH₃)₂—CN, and-halogen.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀, R₂₀′, L₁,E, G, Z, Q, and n as herein before or below defined,

wherein R₇ is selected from among —C₅-C₆-aryl, and —C₅-C₆-heteroaryl,

wherein the ring R₇ is optionally substituted with one or more groupsselected from among —CF₃, —O—CF₃, —S—CF₃, —CN, -methyl, —F, —Cl,—C(CH₃)₂—CN, and —Br.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, L₁, E, G, Z,Q, and n as herein before or below defined,

wherein R₇ is selected from among —C₅-C₆-aryl, and —C₅-C₆-heteroaryl,

wherein the ring R₇ is optionally substituted with one or more groupsselected from among —CF₃, —O—CF₃, —CN, -methyl, —F, —Cl, —C(CH₃)₂—CN,and —Br.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′ R₁₂,R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₉, R₁₉′, R₂₀, R₂₀′, E, G, Q, andn as herein before or below defined,

wherein Z is C,

and R₄ denotes —H and R₅ is a group of the structure -L₁-R₁₈,

wherein L₁ is selected from among —NH—, —N(CH₃)—, —N(C₂H₅)—, andoptionally a bond and wherein R₁₈ is selected from among—C₆-heterocyclyl comprising 1 or 2 hetero atoms selected from among N,and O,

and wherein R₁₈ is optionally substituted by one or more groups selectedfrom among among —F, —CF₃, —OCF₃, —CN, —OH, —O—CH₃, —CH₃, —NH—C(O)—CH₃,—N(CH₃)—C(O)—CH₃, —C(O)—CH₃, —S(O)₂—CH₃, —NH—S(O)₂—CH₃,—N(CH₃)—S(O)₂—CH₃, —N(CH₃)—S(O)₂—CH₂—CH₃, and —C(O)—O—C₂H₅, morepreferred wherein R₁₈ is optionally substituted by one or more groupsselected from among —F, —O—CH₃, —N(CH₃)—S(O)₂—CH₃, more preferredwherein R₁₈ is optionally substituted by one or more groups selectedfrom among —O—CH₃, —N(CH₃)—S(O)₂—CH₃, more preferred wherein R₁₈ isoptionally substituted by one or more groups selected from among —F, and—O—CH₃, most preferred wherein R₁₈ is optionally substituted by —O—CH₃.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′ R₁₂,R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₉, R₁₉′, E, G, Q, and n as hereinbefore or below defined,

wherein Z is C,

and R₄ denotes —H and R₅ is a group of the structure -L₁-R₁₈,

wherein L₁ is selected from among —NH—, —N(CH₃)—, and —N(C₂H₅)—,

and wherein R₁₈ is selected from among —C₆-heterocyclyl comprising 1 or2 hetero atoms selected from among N, and O,

and wherein R₁₈ is optionally substituted by one or more groups selectedfrom among among —F, —CF₃, —OCF₃, —CN, —OH, —O—CH₃, —CH₃, —NH—C(O)—CH₃,—N(CH₃)—C(O)—CH₃, —C(O)—CH₃, —S(O)₂—CH₃, —NH—S(O)₂—CH₃,—N(CH₃)—S(O)₂—CH₃, —N(CH₃)—S(O)₂—CH₂—CH₃, and —C(O)—O—C₂H₅, morepreferred wherein R₁₈ is optionally substituted by one or more groupsselected from among —O—CH₃, —N(CH₃)—S(O)₂—CH₃, most preferred whereinR₁₈ is optionally substituted by —O—CH₃.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′ R₁₂,R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, E, G, Q, and n as herein before orbelow defined,

wherein Z is C,

and R₄ and R₅ are independently selected from among —H, —C₁-C₆-alkyl,and —N(R₁₉,R₁₉′), wherein R₁₉ and R₁₉′ together form a —C₂-C₆-alkylenegroup, preferably a —C₄-C₅-alkylene group, more preferably a—C₅-alkylene group such that a ring is formed,

wherein such ring is optionally substituted by one or more groupsselected from among among —F, —CF₃, —OCF₃, —CN, —OH, —O—CH₃, —CH₃,—NH—C(O)—CH₃, —N(CH₃)—C(O)—CH₃, —C(O)—CH₃, —S(O)₂—CH₃, —NH—S(O)₂—CH₃,—N(CH₃)—S(O)₂—CH₃, —N(CH₃)—S(O)₂—CH₂—CH₃, and —(C₆-aryl)-COOH,—C(O)—O—C₂H₅, more preferred wherein such ring is optionally substitutedby one or more groups selected from among —O—CH₃, —NH—S(O)₂—CH₃,—(C₆-aryl)-COOH, and —N(CH₃)—S(O)₂—CH₃, more preferred wherein such ringis optionally substituted by one or more groups selected from among—O—CH₃, —NH—S(O)₂—CH₃, and —N(CH₃)—S(O)₂—CH₃, more preferred whereinsuch ring is optionally substituted by one or more groups selected fromamong —(C₆-aryl)-COOH, and —N(CH₃)—S(O)₂—CH₃, most preferred whereinsuch ring is optionally substituted by —N(CH₃)—S(O)₂—CH₃.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′ R₁₂,R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, E, G, Q, and n as herein before orbelow defined,

wherein Z is C,

and R₄ and R₅ are independently selected from among —H, —C₁-C₆-alkyl,and —N(R₁₉,R₁₉′), wherein R₁₉ and R₁₉′ together form a —C₂-C₆-alkylenegroup, preferably a —C₄-C₅-alkylene group, more preferably a—C₅-alkylene group such that a ring is formed,

wherein such ring is optionally substituted by —(C₆-aryl)-COOH.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′ R₁₂,R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, E, G, Q, and n as herein before orbelow defined,

wherein Z is C,

and R₄ and R₅ are independently selected from among —H, —C₁-C₆-alkyl,and —N(R₁₉,R₁₉′), wherein R₁₉ and R₁₉′ together form a —C₂-C₆-alkylenegroup, preferably a —C₅-C₆-alkylene group such that a ring is formed,

wherein such ring is optionally substituted by one or more groupsselected from among among —F, —CF₃, —OCF₃, —CN, —OH, —O—CH₃, —CH₃,—NH—C(O)—CH₃, —N(CH₃)—C(O)—CH₃, —C(O)—CH₃, —S(O)₂—CH₃, —NH—S(O)₂—CH₃,—N(CH₃)—S(O)₂—CH₃, —N(CH₃)—S(O)₂—CH₂—CH₃, and —C(O)—O—C₂H₅, morepreferred wherein such ring is optionally substituted by one or moregroups selected from among —O—CH₃, —NH—S(O)₂—CH₃, and —N(CH₃)—S(O)₂—CH₃,most preferred wherein such ring is optionally substituted by—N(CH₃)—S(O)₂—CH₃.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀, R₂₀′, L₁,E, G, Z, Q, and n as herein before or below defined,

wherein R₂ is selected from among —H, -methyl, -ethyl, -propyl,-i-propyl, -butyl, -i-butyl, -t-butyl, —F, —Cl, —Br, —I, —CN, —CH═CH₂,and —C≡CH, more preferred wherein R₂ is selected from among —H, -Methyl,-Ethyl, and —Br, more preferred wherein R₂ is selected from among —H,and -Methyl, most preferred wherein R₂ denotes -Methyl.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, L₁, E, G, Z,Q, and n as herein before or below defined,

wherein R₂ is selected from among —H, -methyl, -ethyl, -propyl,-i-propyl, -butyl, -i-butyl, -t-butyl, —F, —Cl, —Br, —I, —CN, —CH═CH₂,and —C≡CH, more preferred wherein R₂ is selected from among —H, -Methyl,-Ethyl, and —Br, more preferred wherein R₂ is selected from among —H,and -Methyl, most preferred wherein R₂ denotes -Methyl.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀, R₂₀′, L₁,E, G, Z, Q, and n as herein before or below defined,

wherein R₂ denotes —H.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, L₁, E, G, Z,Q, and n as herein before or below defined,

wherein R₂ denotes —H.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁,R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀,R₂₀′, L₁, E, G, Z, Q, and n as herein before or below defined,

wherein R₃ is selected from among —H, -methyl, -ethyl, -propyl,-i-propyl, -cyclopropyl, —OCH₃, —CF₃, and —CN.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁,R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, L₁, E, G,Z, Q, and n as herein before or below defined,

wherein R₃ is selected from among —H, -methyl, -ethyl, -propyl,-i-propyl, -cyclopropyl, —OCH₃, —CF₃, and —CN

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁,R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀,R₂₀′, L₁, E, G, Z, Q, and n as herein before or below defined,

wherein R₃ is selected from among —OCH₃, —H, —CF₃, and -methyl, morepreferred wherein R₃ is selected from among —H, and -methyl, morepreferred wherein R₃ denotes —H.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁,R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀,R₂₀′, L₁, E, G, Z, Q, and n as herein before or below defined,

wherein R₃ denotes —OCH₃.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁,R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀,R₂₀′, L₁, E, G, Z, Q, and n as herein before or below defined,

wherein R₃ denotes —CF₃.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁,R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, L₁, E, G,Z, Q, and n as herein before or below defined,

wherein R₃ is selected from among —H, —CF₃, and -methyl, more preferredwherein R₃ is selected from among —H, and -methyl, more preferredwherein R₃ denotes —H.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′ R₁₂,R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀, R₂₀′, L₁, E,G, Q, and n as herein before or below defined,

wherein Z is C,

R₄ denotes —H, and R₅ is selected from among

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′ R₁₂,R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀, R₂₀′, L₁, E,G, Q, and n as herein before or below defined,

wherein Z is C,

and R₄ denotes —H, and R₅ denotes —N(R₁₉,R₁₉′), wherein R₁₉ and R₁₉′together form a —C₂-C₆-alkylene group such that a ring is formed, morepreferred wherein R₁₉ and R₁₉′ together form a —C₄-C₅-alkylene groupsuch that a ring is formed, most preferred wherein R₁₉ and R₁₉′ togetherform a —C₅-alkylene group such that a ring is formed,

wherein such ring is optionally substituted by one or more groupsselected from among among —F, —CF₃, —OCF₃, —CN, —OH, —O—CH₃, —CH₃,—NH—C(O)—CH₃, —N(CH₃)—C(O)—CH₃, —C(O)—CH₃, —S(O)₂—CH₃, —NH—S(O)₂—CH₃,—N(CH₃)—S(O)₂—CH₃, —(C₆-aryl)-COOH, —N(CH₃)—S(O)₂—CH₂—CH₃, and—C(O)—O—C₂H₅, more preferred wherein such ring is optionally substitutedby one or more groups selected from among —O—CH₃, —NH—S(O)₂—CH₃,—(C₆-aryl)-COOH, and —N(CH₃)—S(O)₂—CH₃, more preferred wherein such ringis optionally substituted by one or more groups selected from among—(C₆-aryl)-COOH, and —N(CH₃)—S(O)₂—CH₃, most preferred wherein such ringis optionally substituted by —N(CH₃)—S(O)₂—CH₃.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′ R₁₂,R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, L₁, E, G, Q, and nas herein before or below defined,

wherein Z is C,

and R₄ denotes —H, and R₅ denotes —N(R₁₉,R₁₉′), wherein R₁₉ and R₁₉′together form a —C₂-C₆-alkylene group such that a ring is formed, morepreferred wherein R₁₉ and R₁₉′ together form a —C₅-C₆-alkylene groupsuch that a ring is formed, most preferred wherein R₁₉ and R₁₉′ togetherform a —C₅-alkylene group such that a ring is formed,

wherein such ring is optionally substituted by one or more groupsselected from among among —F, —CF₃, —OCF₃, —CN, —OH, —O—CH₃, —CH₃,—NH—C(O)—CH₃, —N(CH₃)—C(O)—CH₃, —C(O)—CH₃, —S(O)₂—CH₃, —NH—S(O)₂—CH₃,—N(CH₃)—S(O)₂—CH₃, —N(CH₃)—S(O)₂—CH₂—CH₃, and —C(O)—O—C₂H₅, morepreferred wherein such ring is optionally substituted by one or moregroups selected from among —O—CH₃, —NH—S(O)₂—CH₃, and —N(CH₃)—S(O)₂—CH₃,most preferred wherein such ring is optionally substituted by—N(CH₃)—S(O)₂—CH₃.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀, R₂₀′, L₁,E, G, Z, Q, and n as herein before or below defined,

wherein R₄ is selected from among —H, and —C(O)—NH2, more preferredwherein R₄ denotes —H.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀, R₂₀′, L₁,E, G, Z, Q, and n as herein before or below defined,

wherein R₅ is selected from among —H, and —C(O)—NH2, more preferredwherein R₅ denotes —H.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, L₁, E, G, Z,Q, and n as herein before or below defined,

wherein R₅ is selected from among —H, and —C(O)—NH2, more preferredwherein R₅ denotes —H.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁,R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀,R₂₀′, E, G, Z, Q, and n as herein before or below defined,

wherein L₁ denotes a bond.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀, R₂₀′, L₁,E, G, Z, Q, and n as herein before or below defined,

wherein R₆ is selected from among —H, —CH₃, —C₂H₅, —O—CH₃, —O—C₂H₅, —F,—CF₃, and —OCF₃, more preferred wherein R₆ is —H or —O—CH₃, mostpreferred wherein R₆ denotes —H.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, L₁, E, G, Z,Q, and n as herein before or below defined,

wherein R₆ is selected from among —H, —CH₃, —C₂H₅, —O—CH₃, —O—C₂H₅, —F,—CF₃, and —OCF₃, more preferred wherein R₆ is —H or —O—CH₃, mostpreferred wherein R₆ denotes —H.

Preferred compounds of formula (I) according to the invention arecompounds with R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀, R₂₀′, L₁,E, G, Z, Q, and n as herein before or below defined, wherein R₁ is —H.

Preferred compounds of formula (I) according to the invention arecompounds with R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, L₁, E, G, Z,Q, and n as herein before or below defined, wherein R₁ is —H.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁,R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀,R₂₀′, L₁, E, G, Z, and Q, as herein before or below defined, wherein nis 2.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁,R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, L₁, E, G,Z, and Q, as herein before or below defined, wherein n is 2.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁,R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀,R₂₀′, L₁, Z, Q, and n as herein before or below defined, wherein G and Eare N.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁,R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, L₁, Z, Q,and n as herein before or below defined, wherein G and E are N.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁,R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀,R₂₀′, L₁, Z, Q, and n as herein before or below defined, wherein G isC—H, and E is N.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁,R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, L₁, Z, Q,and n as herein before or below defined, wherein G is C—H, and E is N.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁,R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀,R₂₀′, L₁, Z, Q, and n as herein before or below defined, wherein E isC—H, and G is N.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁,R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, L₁, Z, Q,and n as herein before or below defined, wherein E is C—H, and G is N.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁,R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀,R₂₀′, L₁, E, G, Q, and n as herein before or below defined, wherein Z isC.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁,R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, L₁, E, G,Q, and n as herein before or below defined, wherein Z is C.

The present invention also relates to process for preparing a compoundof formula (I) as herein before or below defined, wherein R₁, R₂, R₃,R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄,R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀, R₂₀′, L₁, Z, E, G, Q, and nhave the meanings defined hereinbefore.

The present invention also relates to the following intermediateproducts for synthesizing the compounds of formula (I) according to theinvention:

-   -   compounds according to formula (II) according to preparation        method A,    -   compounds according to formula (III) according to preparation        method A,    -   compounds according to formula (V) according to preparation        method B,    -   compounds according to formula (VI) according to preparation        method B,    -   compounds according to formula (VIII) according to preparation        method C,    -   compounds according to formula (X) according to preparation        method D,    -   compounds according to formula (XI) according to preparation        method D,    -   compounds according to formula (XIII) according to preparation        method E,    -   compounds according to formula (XIV) according to preparation        method E,

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀, R₂₀′,R₂₁, R₂₁′, L₁, E, G, Q, Z, CYC, and n have the meanings definedhereinbefore.

The present invention also relates to the following intermediateproducts according to general formula (XVI) for synthesizing thecompounds of formula (I) according to the invention

wherein R₂₂ is a group selected from among —H, —CF₃, —O—CF₃, —S—CF₃,—CN, —C₁-C₆-alkyl, —C(CH₃)₂—CN, and -halogen

or wherein R₂₂ is a group selected from among —C₁-C₆-alkyl,—O—C₁-C₆-alkyl, —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl, —C₃-C₈-cycloalkyl,—C₃-C₈-heterocyclyl, —C₂-C₆-alkenyl, and —C₂-C₆-alkynyl, optionallybeing substituted by one or more groups selected from among —OH, —NH₂,—C₁-C₃-alkyl, —O—C₁-C₆-alkyl, —CN, —CF₃, —OCF₃, halogen, -methyl, and═O,

more preferred wherein R₂₂ is a group selected from among —CF₃, —O—CF₃,—S—CF₃, —CN, -methyl, —C(CH₃)₂—CN, and -halogen, more preferred whereinR₂₂ is a group selected from among —CF₃, —O—CF₃, —S—CF₃, —CN, -methyl,—F, —Cl, —C(CH₃)₂—CN, and —Br,

and wherein R₂₃ is a group selected from among —H and —C₁-C₃-alkyl, morepreferred wherein R₂₃ denotes —H.

The present invention also relates to the following intermediateproducts according to general formula (XVII) for synthesizing thecompounds of formula (I) according to the invention

wherein R₂₂ is a group selected from among —H, —CF₃, —O—CF₃, —S—CF₃,—CN, —C₁-C₆-alkyl, —C(CH₃)₂—CN, and -halogen, or wherein R₂₂ is a groupselected from among —C₁-C₆-alkyl, —O—C₁-C₆-alkyl, —C₅-C₁₀-aryl,—C₅-C₁₀-heteroaryl, —C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl,—C₂-C₆-alkenyl, and —C₂-C₆-alkynyl, optionally being substituted by oneor more groups selected from among —OH, —NH₂, —C₁-C₃-alkyl,—O—C₁-C₆-alkyl, —CN, —CF₃, —OCF₃, halogen, -methyl, and ═O, morepreferred wherein R₂₂ is a group selected from among —CF₃, —O—CF₃,—S—CF₃, —CN, -methyl, —C(CH₃)₂—CN, and -halogen, more preferred whereinR₂₂ is a group selected from among —CF₃, —O—CF₃, —S—CF₃, —CN, -methyl,—F, —Cl, —C(CH₃)₂—CN, and —Br, and wherein R₂ is a group selected fromamong —H, -halogen, —CN, —O—C₂-C₄-alkyl, —C₁-C₄-alkyl, —CH═CH₂, —C≡CH,—CF₃, —OCF₃, —OCF₂H, and —OCFH₂ , more preferred wherein R₂ is a groupselected from among —H, -methyl, -ethyl, -propyl, -i-propyl, -butyl,-i-butyl, -t-butyl, —F, —Cl, —Br, —I, —CN, —CH═CH₂, and —C≡CH, morepreferred wherein R₂ is a group selected from among —H, -Methyl, -Ethyl,and —Br, more preferred wherein R₂ is selected from among —H, and-Methyl, most preferred wherein R₂ denotes -Methyl or wherein R₂ denotes—H; and wherein R₃ is a group selected from among —H, -methyl, -ethyl,-propyl, -i-propyl, -cyclopropyl, —OCH₃, —CF₃, and —CN, more preferredwherein R₃ is a group selected from among —H, —CF₃, —O—CH₃, and -methyl,more preferred wherein R₃ is selected from among —H, —O—CH₃, and-methyl, more preferred wherein R₃ denotes —H, or wherein R₃ denotes—O—CH₃, or wherein R₃ denotes —CF₃; and wherein G and E areindependently selected from among C—H or N, more preferred wherein Gdenotes C—H and E denotes N, more preferred wherein G denotes N and Edenotes C—H, most preferred wherein G and E are N.

The present invention also relates to process for preparing a compoundof formula (II) according to preparation method A wherein R₁, R₂, R₃,R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄,R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀, R₂₀′, L₁, E, G, Z, Q, and nhave the meanings defined hereinbefore.

The present invention also relates to process for preparing a compoundof formula (III) according to preparation method A wherein R₁, R₂, R₃,R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄,R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀, R₂₀′, L₁, E, G, Z, Q, and nhave the meanings defined hereinbefore.

The present invention also relates to process for preparing a compoundof formula (V) according to preparation method B wherein R₁, R₂, R₃, R₄,R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅,R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀, R₂₀′, L₁, E, G, Z, Q, and n havethe meanings defined hereinbefore.

The present invention also relates to process for preparing a compoundof formula (VI) according to preparation method B wherein R₁, R₂, R₃,R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄,R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀, R₂₀′, L₁, E, G, Z, Q, and nhave the meanings defined hereinbefore.

The present invention also relates to process for preparing a compoundof formula (VIII) according to preparation method C wherein R₁, R₂, R₃,R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄,R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀, R₂₀′, L₁, E, G, Z, Q, and nhave the meanings defined hereinbefore.

The present invention also relates to process for preparing a compoundof formula (X) according to preparation method D wherein R₁, R₂, R₃, R₄,R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅,R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀, R₂₀′, L₁, E, G, Z, Q, and n havethe meanings defined hereinbefore.

The present invention also relates to process for preparing a compoundof formula (XI) according to preparation method D wherein R₁, R₂, R₃,R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄,R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀, R₂₀′, R₂₁, R₂₁′, L₁, L₂, E, G,Z, Y₁, Q, and n have the meanings defined hereinbefore.

The present invention also relates to process for preparing a compoundof formula (XIII) according to preparation method E wherein R₁, R₂, R₃,R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄,R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀, R₂₀′, L₁, E, G, Z, Q, and nhave the meanings defined hereinbefore.

The present invention also relates to process for preparing a compoundof formula (XIV) according to preparation method E wherein R₁, R₂, R₃,R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄,R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′, R₂₀, R₂₀′, R₂₁, R₂₁′, L₁, E, G, Z,Q, CYC, and n have the meanings defined hereinbefore.

All of the above embodiments under formula (I) have to be understood tooptionally be present in form of their individual optical isomers,mixtures of their individual optical isomers, or racemates, as well asin form of their acid addition salts with pharmacologically acceptableacids, as well as in form of their solvates and/or hydrates.

It has now been found that such compounds as herein before or belowdefined could be used as a medicament.

It has been found that such compounds as herein before or below definedcould be used for making a medicament for the treatment of inflammatorydiseases. It has been found that such compounds as herein before orbelow defined could be used for making a medicament for the treatment ofinflammatory diseases, wherein the inflammatory diseases are selectedfrom inflammatory diseases of the respiratory tract. It has been foundthat such compounds as herein before or below defined could be used formaking a medicament for the treatment of inflammatory diseases, whereinthe inflammatory diseases are selected from chronic obstructivepulmonary disease, asthma, and cystic fibrosis. It has been found thatsuch compounds as herein before or below defined could be used formaking a medicament for the treatment of neurologic diseases, preferablyfor the treatment of pain diseases especially for the treatment ofinflammatory and neuropathic pain disease, especially for the treatmentof chronic pain. It has been found that such compounds as herein beforeor below defined could be used for making a medicament for the treatmentof immune related diseases, preferably for the treatment of diabetesmellitus. It has been found that such compounds as herein before orbelow defined could be used for making a medicament for the treatment ofcardiovascular diseases, preferably for the treatment of peripheralatherosclerotic disease. It has been found that such compounds as hereinbefore or below defined could be used for making a medicament for thetreatment of diabetic nephropathy.

Present invention encloses compounds as herein before or below definedas medicaments. Present invention encloses compounds as herein before orbelow defined as medicaments for the treatment of inflammatory diseases.Present invention encloses compounds as herein before or below definedas medicaments for the treatment of inflammatory diseases, wherein theinflammatory diseases are selected from inflammatory diseases of therespiratory tract. Present invention encloses compounds as herein beforeor below defined as medicaments for the treatment of inflammatorydiseases, wherein the inflammatory diseases are selected from chronicobstructive pulmonary disease, asthma, and cystic fibrosis. Presentinvention encloses compounds as herein before or below defined asmedicaments for the treatment of neurologic diseases, preferably for thetreatment of pain diseases especially for the treatment of inflammatoryand neuropathic pain disease, especially for the treatment of chronicpain. Present invention encloses compounds as herein before or belowdefined as medicaments for the treatment of immune related diseases,preferably for the treatment of diabetes mellitus. Present inventionencloses compounds as herein before or below defined as medicaments forthe treatment of cardiovascular diseases, preferably for the treatmentof peripheral atherosclerotic disease. Present invention enclosescompounds as herein before or below defined as medicaments for thetreatment of diabetic nephropathy.

It has been found that such compounds as herein before or below definedcould be used for the treatment of inflammatory diseases. It has beenfound that such compounds as herein before or below defined could beused for the treatment of inflammatory diseases, wherein theinflammatory diseases are selected from inflammatory diseases of therespiratory tract. It has been found that such compounds as hereinbefore or below defined could be used for the treatment of inflammatorydiseases, wherein the inflammatory diseases are selected from chronicobstructive pulmonary disease, asthma, and cystic fibrosis. It has beenfound that such compounds as herein before or below defined could beused for the treatment of neurologic diseases, preferably for thetreatment of pain diseases especially for the treatment of inflammatoryand neuropathic pain disease, especially for the treatment of chronicpain. It has been found that such compounds as herein before or belowdefined could be used for the treatment of immune related diseases,preferably for the treatment of diabetes mellitus. It has been foundthat such compounds as herein before or below defined could be used forthe treatment of cardiovascular diseases, preferably for the treatmentof peripheral atherosclerotic disease. It has been found that suchcompounds as herein before or below defined could be used for thetreatment of diabetic nephropathy.

Definitions

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, —C₁-C₆-alkylmeans an alkyl group or radical having 1 to 6 carbon atoms. In general,for groups comprising two or more subgroups, the last named subgroup isthe radical attachment point, for example, the substituent“aryl-C₁-C₃-alkyl-” means an aryl group which is bound to aC₁-C₃-alkyl-group, the latter of which is bound to the core or to thegroup to which the substituent is attached.

In case a compound of the present invention is depicted in form of achemical name and as a formula in case of any discrepancy the formulashall prevail. An asterisk is may be used in sub-formulas to indicatethe bond which is connected to the core molecule as defined.

For example, the term “3-carboxypropyl-group” represents the followingsubstituent:

wherein the carboxy group is attached to the third carbon atom of thepropyl group. The terms “1-methylpropyl-”, “2,2-dimethylpropyl-” or“cyclopropylmethyl-” group represent the following groups:

The asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

Many of the followings terms may be used repeatedly in the definition ofa formula or group and in each case have one of the meanings givenabove, independently of one another.

Unless otherwise stated, all the substituents are independent of oneanother. If for example there might be a plurality of C₁-C₆-alkyl groupsas substituents in one group, in the case of three substituentsC₁-C₆-alkyl, one may represent methyl, one n-propyl and one tert-butyl.

Within the scope of this application, in the definition of possiblesubstituents, these may also be represented in the form of a structuralformula. An asterisk (*) in the structural formula of the substituent isto be understood as being the linking point to the rest of the molecule.Moreover, the atom of the substituent which follows the linking point isreferred to as the atom in position number 1. Thus, for example, thegroups N-piperidinyl (Piperidin-A), 4-piperidinyl (Piperidin-B), 2-tolyl(Tolyl-C), 3-tolyl (Tolyl-D), and 4-tolyl (Tolyl-E) are shown asfollows:

If there is no asterisk (*) in the structural formula of thesubstituent, each hydrogen atom may be removed from the substituent andthe valency thus freed may act as a binding site to the rest of amolecule. Thus, for example, (Tolyl-F) may represent 2-tolyl, 3-tolyl,4-tolyl, and benzyl

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valence isnot exceeded, and that the substitution results in a stable compound.

By the term “optionally substituted” is meant within the scope of theinvention the above-mentioned group, optionally substituted by alower-molecular group. Examples of lower-molecular groups regarded aschemically meaningful are groups consisting of 1-200 atoms. Preferablysuch groups have no negative effect on the pharmacological efficacy ofthe compounds. For example the groups may comprise:

-   -   Straight-chain or branched carbon chains, optionally interrupted        by heteroatoms, optionally substituted by rings, heteroatoms or        other common functional groups.    -   Aromatic or non-aromatic ring systems consisting of carbon atoms        and optionally heteroatoms, which may in turn be substituted by        functional groups.    -   A number of aromatic or non-aromatic ring systems consisting of        carbon atoms and optionally heteroatoms which may be linked by        one or more carbon chains, optionally interrupted by        heteroatoms, optionally substituted by heteroatoms or other        common functional groups.

By the term “branched or unbranched, saturated or unsaturatedC₁-C₆-carbon chain” it is meant a chain of carbon atoms, which isconstituted by 1 to 6 carbon atoms arranged in a row and which canoptionally further comprise branches or one or more hetero atomsselected from N, O or S. Said carbon chain can be saturated orunsaturated by comprising double or triple bonds.

If the carbon chain is to be substituted by a group which together withone or two carbon atoms of the alkylene chain forms a carbocyclic ringwith 3, 5 or 6 carbon atoms, this includes the following examples of therings:

The term “C₁-C_(n)-alkyl”, wherein n is an integer from 2 to n, eitheralone or in combination with another radical denotes an acyclic,saturated, branched or linear hydrocarbon radical with 1 to n C atoms.For example the term C₁-C₅-alkyl embraces the radicals H₃C—, H₃C—CH₂—,H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—,H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—,H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—,H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— andH₃C—CH₂—CH(CH₂CH₃)—.

By the term “C₁-C₆-alkyl” (including those which are part of othergroups) are meant branched and unbranched alkyl groups with 1 to 6carbon atoms and by the term “C₁-C₄-alkyl” are meant branched andunbranched alkyl groups with 1 to 4 carbon atoms. Alkyl groups with 1 to4 carbon atoms are preferred. By the term “C₁-C₃-alkyl” are meantbranched and unbranched alkyl groups with 1 to 3 carbon atoms and by theterm “C₂-C₄-alkyl” are meant branched and unbranched alkyl groups with 2to 4 carbon atoms. Examples for alkyl groups with 1-6 carbon atomsinclude: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl or hexyl.Optionally the abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc.may also be used for the above-mentioned groups. Unless statedotherwise, the definitions propyl, butyl, pentyl and hexyl include allthe possible isomeric forms of the groups in question. Thus, forexample, propyl includes n-propyl and iso-propyl, butyl includesiso-butyl, sec-butyl and tert-butyl etc.

The term “C₁-C_(n)-alkylene” wherein n is an integer 2 to n, eitheralone or in combination with another radical, denotes an acyclic,straight or branched chain divalent alkyl radical containing from 1 to ncarbon atoms. For example the term C₁-C₄-alkylene includes —CH₂—,—CH₂—CH₂—, —CH(CH₃)—, —CH₂—CH₂—CH₂—, —C(CH₃)₂—, —CH(CH₂CH₃)—,—CH(CH₃)—CH₂—, —CH₂—CH(CH₃)—, —CH₂—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH(CH₃)—,—CH(CH₃)—CH₂—CH₂—, —CH₂—CH(CH₃)—CH₂—, —CH₂—C(CH₃)₂—, —C(CH₃)₂—CH₂—,—CH(CH₃)—CH(CH₃)—, —CH₂—CH(CH₂CH₃)—, —CH(CH₂CH₃)—CH₂—, —CH(CH₂CH₂CH₃)—,—CH(CH(CH₃))₂— and —C(CH₃)(CH₂CH₃)—.

By the term “C₁-C₈-alkylene” (including those which are part of othergroups) are meant branched and unbranched alkylene groups with 1 to 8carbon atoms. By the term “C₂-C₈-alkylene” are meant branched andunbranched alkylene groups with 2 to 8 carbon atoms. By the term“C₂-C₆-alkylene” are meant branched and unbranched alkylene groups with2 to 6 carbon atoms. By the term “C₁-C₄-alkylene” are meant branched andunbranched alkylene groups with 1 to 4 carbon atoms. By the term“C₁-C₂-alkylene” are meant branched and unbranched alkylene groups with1 to 2 carbon atoms. By the term “C₀-C₄-alkylene” are meant branched andunbranched alkylene groups with 0 to 4 carbon atoms, thus also a singlebond is encompassed. By the term “C₁-C₃-alkylene” are meant branched andunbranched alkylene groups with 1 to 3 carbon atoms. Examples forC₁-C₈-alkylene include: methylene, ethylene, propylene,1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene,1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene,2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene,hexylene, heptylene or octylene. Unless stated otherwise, thedefinitions propylene, butylene, pentylene, hexylene, heptylene andoctylene include all the possible isomeric forms of the groups inquestion with the same number of carbons. Thus, for example, propyl alsoincludes 1-methylethylene and butylene includes 1-methylpropylene,1,1-dimethylethylene, 1,2-dimethylethylene.

The term “C₂-C_(n)-alkenyl”, is used for a group as defined in thedefinition for “C₁-C_(n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a double bond.

By the term “C₂-C₆-alkenyl” (including those which are part of othergroups) are meant branched and unbranched alkenyl groups with 2 to 6carbon atoms and by the term “C₂-C₄-alkenyl” are meant branched andunbranched alkenyl groups with 2 to 4 carbon atoms, provided that theyhave at least one double bond. Alkenyl groups with 2 to 4 carbon atomsare preferred. Examples for C₂-C₆-alkenyls include: ethenyl or vinyl,propenyl, butenyl, pentenyl, or hexenyl. Unless stated otherwise, thedefinitions propenyl, butenyl, pentenyl and hexenyl include all thepossible isomeric forms of the groups in question. Thus, for example,propenyl includes 1-propenyl and 2-propenyl, butenyl includes 1-, 2- and3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl etc.

By the term “methenylene” is meant a group with 1 carbon atom, providedthat it is linked by a single bond as well as on the other side by adouble bond. The asterisks (*) in the structural formula is to beunderstood as being the linking points to the rest of the molecule,whereas the valency of the rest of the molecule be freed thus a singleand a double bond can be formed by replacement of further hydrogens atthe binding site if applicable:

The term “C₂-C_(n)-alkenylene” is used for a group as defined in thedefinition for “C₁-C_(n)-alkylene” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a double bond.

By the term “C₂-C₈-alkenylene” (including those which are part of othergroups) are meant branched and unbranched alkenylene groups with 2 to 8carbon atoms and by the term “C₂-C₆-alkenylene” are meant branched andunbranched alkenylene groups with 2 to 6 carbon atoms. By the term“C₁-C₂-alkenylene” are meant alkenylene groups with 1 to 2 carbon atoms,provided that they have at least one double bond, whereas by the term“C₁-alkenylene” is meant “methenylene”. Examples for C₂-C₈-alkenylenesinclude: ethenylene, propenylene, 1-methylethenylene, butenylene,1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene,pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene,1,2-dimethylpropenylene, 1,3-dimethylpropenylene, hexenylene,heptenylene or octenylene. Unless stated otherwise, the definitionspropenylene, butenylene, pentenylene and hexenylene include all thepossible isomeric forms of the groups in question with the same numberof carbons. Thus, for example, propenyl also includes 1-methylethenyleneand butenylene includes 1-methylpropenylene, 1,1-dimethylethenylene,1,2-dimethylethenylene.

The term “C₂-C_(n)-alkynyl”, is used for a group as defined in thedefinition for “C₁-C_(n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a triple bond.

By the term “C₂-C₆-alkynyl” (including those which are part of othergroups) are meant branched and unbranched alkynyl groups with 2 to 6carbon atoms and by the term “C₂-C₄-alkynyl” are meant branched andunbranched alkynyl groups with 2 to 4 carbon atoms, provided that theyhave at least one triple bond. Examples for C₂-C₆-alkynyls include:ethynyl, propynyl, butynyl, pentynyl or hexynyl. Unless statedotherwise, the definitions propynyl, butynyl, pentynyl and hexynylinclude all the possible isomeric forms of the groups in question. Thusfor example propynyl includes 1-propynyl and 2-propynyl, butynylincludes 1-, 2-, and 3-butynyl, 1-methyl-1-propynyl, 1-methyl-2-propynyletc.

The term “C₂-C_(n)-alkynylene” is used for a group as defined in thedefinition for “C₁-C_(n)-alkylene” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a triple bond.

By the term “C₂-C₈-alkynylene” (including those which are part of othergroups) are meant branched and unbranched alkynylene groups with 2 to 8carbon atoms and by the term “C₂-C₆-alkynylene” are meant branched andunbranched alkynylene groups with 2 to 6 carbon atoms. Examples ofC₂-C₈-alkynylenes include: ethynylene, propynylene, 1-methylethynylene,butynylene, 1-methylpropynylene, 1,1-dimethylethynylene,1,2-dimethylethynylene, pentynylene, 1,1-dimethylpropynylene,2,2-dimethylpropynylene, 1,2-dimethylpropynylene,1,3-dimethylpropynylene, hexynylene, heptynylene or octynylene. Unlessstated otherwise, the definitions propynylene, butynylene, pentynyleneand hexynylene include all the possible isomeric forms of the groups inquestion with the same number of carbons. Thus for example propynyl alsoincludes 1-methylethynylene and butynylene includes 1-methylpropynylene,1,1-dimethylethynylene, 1,2-dimethylethynylene.

The term “carbocyclyl” as used either alone or in combination withanother radical, means a mono- bi- or tricyclic ring structureconsisting of 3 to 14 carbon atoms. The term “carbocycle” refers tofully saturated and aromatic ring systems and partially saturated ringsystems. The term “carbocycle” encompasses fused, bridged andspirocyclic systems:

By the term “ring” are meant carbocycles, which can be saturated,unsaturated or aromatic and which optionally can comprise one or morehetero atoms selected from N, O or S.

The term “heterocyclyl” means a saturated or unsaturated mono- orpolycyclic-ring systems including aromatic ring system containing one ormore heteroatoms selected from N, O or S(O)_(r), wherein r=0, 1 or 2,consisting of 3 to 14 ring atoms wherein none of the heteroatoms is partof the aromatic ring. The term “heterocycle” is intended to include allthe possible isomeric forms.

Thus, the term “heterocyclyl” includes the following exemplarystructures which are not depicted as radicals as each form may beattached through a covalent bond to any atom so long as appropriatevalences are maintained:

By the term “—C₃-C₈-heterocyclyl” are meant three-, four-, five-, six-,seven, or eight-membered, saturated or unsaturated heterocyclic ringswhich may contain one, two, or three heteroatoms, selected from amongoxygen, sulfur, and nitrogen, whereas carbon atoms be replaced by suchheteroatoms. The ring may be linked to the molecule through a carbonatom or through a nitrogen atom, if there is one. By the term“—C₅-C₈-heterocyclyl” are meant five-, six-, seven or eight-membered,saturated or unsaturated heterocyclic rings which may contain one, two,or three heteroatoms, selected from among oxygen, sulfur, and nitrogen,while the ring may be linked to the molecule through a carbon atom orthrough a nitrogen atom, if there is one. Examples for C₅-heterocyclylinclude:

Examples for C₆-heterocyclyl include:

Examples for C₇-heterocyclyl include:

Unless otherwise mentioned, a heterocyclic ring (or “heterocycle”) maybe provided with a keto group. Examples include:

The term “C₃-C_(n)-cycloalkyl”, wherein n is an integer from 3 to n,either alone or in combination with another radical denotes a cyclic,saturated, unbranched hydrocarbon radical with 3 to n C atoms. Forexample the term C₃-C₇-cycloalkyl includes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl.

By the term “C₃-C₈-cycloalkyl” (including those which are part of othergroups) are meant cyclic alkyl groups with 3 to 8 carbon atoms.Likewise, by the term “C₃-C₆-cycloalkyl” are meant cyclic alkyl groupswith 3 to 6 carbon atoms. Examples of C₃-C₈-cycloalkyls include:cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl. Unless otherwise stated, the cyclic alkyl groups may besubstituted by one or more groups selected from among methyl, ethyl,isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine, and iodine.

The term “C₃-C_(n)-cycloalkenyl”, wherein n is an integer from 3 to n,either alone or in combination with another radical, denotes an cyclic,unsaturated but nonaromatic, unbranched hydrocarbon radical with 3 to nC atoms, at least two of which are bonded to each other by a doublebond. For example the term C₃₋₇-cycloalkenyl includes cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl,cyclohexadienyl, cycloheptenyl cycloheptadienyl and cycloheptatrienyl.

By the term “aryl” (including those which are part of other groups) aremeant aromatic ring systems.

The term “aryl” as used herein, either alone or in combination withanother radical, denotes a carbocyclic aromatic monocyclic groupcontaining 6 carbon atoms which may be further fused to a second 5- or6-membered carbocyclic group which may be aromatic, saturated orunsaturated. Aryl includes, but is not limited to, phenyl, indanyl,indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl anddihydronaphthyl.

By the term “C₅-C₁₀-aryl” (including those which are part of othergroups) are meant aromatic ring systems with 5 to 10 carbon atoms.Preferred are “C₆-C₁₀-aryl” groups whereas aromatic rings are meant with6 to 10 carbon atoms. Examples include: phenyl or naphthyl. Alsopreferred are “C₅-C₆-aryl” groups whereas aromatic rings are meant with5 to 6 carbon atoms. Further preferred are are “C₆-aryl” groups whereasa aromatic ring is meant with 6 carbon atoms. Unless otherwise stated,the aromatic ring systems may be substituted by one or more groupsselected from among methyl, ethyl, iso-propyl, tert-butyl, hydroxy,fluorine, chlorine, bromine and iodine.

The term “heteroaryl” means a mono- or polycyclic-ring systemscontaining one or more heteroatoms selected from N, O or S(O)_(r),wherein r=0, 1 or 2, consisting of 5 to 14 ring atoms wherein at leastone of the heteroatoms is part of aromatic ring. The term “heteroaryl”is intended to include all the possible isomeric forms.

Thus, the term “heteroaryl” includes the following exemplary structureswhich are not depicted as radicals as each form may be attached througha covalent bond to any atom so long as appropriate valences aremaintained:

By the term “C₅-C₁₀-heteroaryl” (including those which are part of othergroups) are meant five- or six-membered heterocyclic aromatic groups or5-10-membered, bicyclic heteroaryl rings which may contain one, two, orthree heteroatoms selected from among oxygen, sulfur, and nitrogen,whereas carbon atoms be replaced by such heteroatoms, and whereas therings contain so many conjugated double bonds that an aromatic system isformed. The following are examples of five- or six- or nine-memberedheterocyclic aromatic groups:

Preferred are “C₅-C₆-heteroaryl” groups whereas aromatic rings are meantfive- or six-membered heterocyclic aromatic groups. Unless otherwisestated, these heteroaryls may be substituted by one or more groupsselected from among methyl, ethyl, isopropyl, tert-butyl, hydroxy,fluorine, chlorine, bromine, and iodine.

When a generic combined groups are used, for example —X—C₁-C₄-alkyl-with X being a functional group such as —CO—, —NH—, —C(OH)— and thelike, the functional group X can be located at either of the ends of the—C₁-C₄-alkyl chain.

By the term “spiro-C₃-C₈-cycloalkyl” (spiro) are meant 3-8 membered,spirocyclic rings while the ring is linked to the molecule through acarbon atom. By the term “spiro-C₃-C₈-heterocyclyl” (spiro) are meant3-8 membered, spirocyclic rings which may contain one, two, or threeheteroatoms selected from among oxygen, sulfur, and nitrogen, whereascarbon atoms be replaced by such heteroatoms. The ring may be linked tothe molecule through a carbon atom or through a nitrogen atom, if thereis one.

Unless otherwise mentioned, a spirocyclic ring may be provided with anoxo, methyl, or ethyl group. Examples include:

“Halogen” within the scope of the present invention denotes fluorine,chlorine, bromine or iodine. Unless stated to the contrary, fluorine,chlorine and bromine are regarded as preferred halogens.

“Linker” within the scope of the present invention denominates abivalent group or a bond.

The above listed groups and residues can be combined to form morecomplex structures composed from carbon chains and rings or the like.

Compounds of general formula (I) may have acid groups, chiefly carboxylgroups, and/or basic groups such as e.g. amino functions. Compounds ofgeneral formula (I) may therefore occur as internal salts, as salts withpharmaceutically useable inorganic acids such as hydrochloric acid,sulphuric acid, phosphoric acid, sulphonic acid or organic acids (suchas for example maleic acid, fumaric acid, citric acid, tartaric acid oracetic acid) or as salts with pharmaceutically useable bases such asalkali or alklaline earth metal hydroxides or carbonates, zinc orammonium hydroxides or organic amines such as e.g. diethylamine,triethylamine, triethanolamine inter alia.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication, andcommensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. For example,such salts include salts from ammonia, L-arginine, betaine, benethamine,benzathine, calcium hydroxide, choline, deanol, diethanolamine(2,2′-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol,2-aminoethanol, ethylenediamine, N-ethyl-glucamine, hydrabamine,1H-imidazole, lysine, magnesium hydroxide,4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide,1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine(2,2′,2″-nitrilotris(ethanol)), tromethamine, zinc hydroxide, aceticacid, 2.2-dichloro-acetic acid, adipic acid, alginic acid, ascorbicacid, L-aspartic acid, benzenesulfonic acid, benzoic acid,2,5-dihydroxybenzoic acid, 4-acetamido-benzoic acid, (+)-camphoric acid,(+)-camphor-10-sulfonic acid, carbonic acid, cinnamic acid, citric acid,cyclamic acid, decanoic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, ethylenediaminetetraacetic acid, formicacid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonicacid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycine, glycolic acid,hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid,isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, lysine,maleic acid, (−)-L-malic acid, malonic acid, DL-mandelic acid,methanesulfonic acid, galactaric acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,nitric acid, octanoic acid, oleic acid, orotic acid, oxalic acid,palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionicacid, (−)-L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid,sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid. Further pharmaceutically acceptable salts can beformed with cations from metals like aluminium, calcium, lithium,magnesium, potassium, sodium, zinc and the like. (also seePharmaceutical salts, Berge, S. M. et al., J. Pharm. Sci., (1977), 66,1-19).

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha sufficient amount of the appropriate base or acid in water or in anorganic diluent like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile, or a mixture thereof.

As mentioned hereinbefore, the compounds of formula (I) may be convertedinto the salts thereof, particularly for pharmaceutical use, into thephysiologically and pharmacologically acceptable salts thereof. Thesesalts may on the one hand be in the form of the physiologically andpharmacologically acceptable acid addition salts of the compounds offormula (I) with inorganic or organic acids. On the other hand, if R ishydrogen, the compound of formula (I) may also be converted by reactionwith inorganic bases into physiologically and pharmacologicallyacceptable salts with alkali or alkaline earth metal cations as counterion. The acid addition salts may be prepared for example usinghydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lacticacid, citric acid, tartaric acid or maleic acid. It is also possible touse mixtures of the above-mentioned acids. The alkali and alkaline earthmetal salts of the compound of formula (I) are preferably prepared usingthe alkali and alkaline earth metal hydroxides and hydrides thereof, ofwhich the hydroxides and hydrides of the alkaline earth metals,particularly of sodium and potassium, are preferred and sodium andpotassium hydroxide are particularly preferred.

If desired, the compounds of general formula (I) may be converted intothe salts thereof, particularly, for pharmaceutical use, into thepharmacologically acceptable acid addition salts with an inorganic ororganic acid. Suitable acids include for example succinic acid,hydrobromic acid, acetic acid, fumaric acid, maleic acid,methanesulphonic acid, lactic acid, phosphoric acid, hydrochloric acid,sulphuric acid, tartaric acid or citric acid. It is also possible to usemixtures of the above-mentioned acids.

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompasstautomers and all stereo, optical and geometrical isomers (e.g.enantiomers, diastereomers, E/Z isomers etc . . . ) and racematesthereof as well as mixtures in different proportions of the separateenantiomers, mixtures of diastereomers, or mixtures of any of theforegoing forms where such isomers and enantiomers exist, as well assalts, including pharmaceutically acceptable salts thereof and solvatesthereof such as for instance hydrates including solvates of the freecompounds or solvates of a salt of the compound.

Hence the invention relates to the compounds in question, optionally inthe form of the individual optical isomers, mixtures of the individualenantiomers or racemates, in the form of the tautomers as well as in theform of the free bases or the corresponding acid addition salts withpharmacologically acceptable acids—such as for example acid additionsalts with hydrohalic acids—for example hydrochloric or hydrobromic acidor organic acids—such as for example oxalic, fumaric, diglycolic ormethanesulphonic acid.

The compounds according to the invention may optionally occur asracemates, but they may also be obtained as pureenantiomers/diastereomers.

The invention relates to the compounds in question, optionally in theform of the individual optical isomers, mixtures of the individualenantiomers or racemates, in the form of the tautomers as well as in theform of the free bases or the corresponding acid addition salts withpharmacologically acceptable acids—such as for example acid additionsalts with hydrohalic acids—for example hydrochloric or hydrobromic acidor organic acids—such as for example oxalic, fumaric, diglycolic ormethanesulphonic acid.

The compounds according to formula (I) according to the invention havethe meanings hereinbefore whereas in particular the preferredembodiments defined by R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₈′, R₉, R₉′,R₁₀, R₁₁, R₁₁′ R₁₂, R₁₃, R₁₃′, R₁₄, R₁₅, R₁₅′, R₁₆, R₁₇, R₁₈, R₁₉, R₁₉′,R₂₀, R₂₀′, L₁, E, G, Z, Q, and n in each case are independently selectedof one another.

Therapeutic Applications

The above exemplary substances have been tested for binding to CCR2using a binding assay as outlined herein below:

Cell Culture:

THP-1 cells (human acute monocytic leukaemia cells) were cultured understandardized conditions at 37° C. and 5% CO2 in a humidified incubator.THP-1 cells were cultivated in RPMI 1640 medium (Gibco 21875) containing1% MEM-NEAA (Gibso 11140) 2 mM L-glutamine, 1.5 g/L sodium bicarbonate,4.5 g/L glucose, 10 mM HEPES and 1.0 mM sodium pyruvate, 90%; 10% fetalcalf serum (FCS Gibco 10500-064).

Membranes were prepared from THP-1 cells. THP-1 cells were centrifugedat 300×g at 4° C. for 10 min. The cell pellet was resuspendet inPhosphate Buffer Saline (PBS, including 10 μM Pefabloc and a proteaseinhibitor mix ‘complete’, Boehringer Mannheim (1 tablet/50 ml)), to aconcentration of 80 cells/ ml. The membrane preparation was performed bydisrupting the cells by nitrogen decomposition (at 50 bar, for 1 h) in a“Nitrogen Bombe” (Parr Instrument). Cell debris was removed bycentrifugation (800×g at 4° C., 1 min). The supernatant was centrifugedat 80000×g, 4° C. for 30 min to sediment the cell membranes. Usually 50mg of protein (Bradford assay) were yielded from 1×10E9 cells. Themembranes were resuspendet in 25 mM HEPES, 25 mM MgCl2, 1 mM CaCl2, 10%Glycerine for storage in aliquots at −80° C. in 25 mM HEPES, 25 mMMgCl2, 1 mM CaCl2, 10% Glycerine and stored at −80° C.

Receptor Membrane Binding Assay:

Perkin Elmer NEX 332 Jod 125 MCP-1, Stock: 2200 Ci/mmol solved in 2000μl assay buffer, stored at −20° C. THP-1 membrane were adjusted with 25mM HEPES, pH 7.2; 5 mM MgCl2; 0.5 mM CaCl2; 0.2% BSA assay buffer to aconcentration of 2.5 μg/15 μl. Amersham Biosciences PVT-WGA Beads(RPNQ0001) were adjusted with assay buffer to a concentration of 0.24mg/30 μl. For preparation of the membrane-bead-suspension membranes andbeads were incubated for 30 min at RT under rotation (60 rpm) with aratio of 1:2. Test compounds dissolved in 100% DMSO to a concentrationof 10 mM and are further diluted with 100% DMSO to 1 mM. All additionalcompound dilutions were obtained with assay buffer, final 1% DMSO.Compounds, membrane-bead-suspension and [125I]MCP-1 (ca. 25000 cpm/10μl) were incubated. Bound radioactivity was determined by scintillationcounter after 8 h. Determination of affinity of test compounds(dissociation constant hKi) is calculated by iterative fitting ofexperimental data using the “easy sys” program, which is based on law ofmass action (Schittkowski K. (1994), Numerische Mathematik, Vol. 68,129-142).

All of the referenced examples have been found to have an activity inthis assay of 10 μM or less.

Example hKi Example hKi  1   8 [nM] 15    24 [nM]  2  151 [nM] 16    11[nM]  3  203 [nM] 17    11 [nM]  4   26 [nM] 18    10 [nM]  5  237 [nM]19   162 [nM]  6  190 [nM] 20    11 [nM]  7   36 [nM] 21    11 [nM]  8 185 [nM] 22    11 [nM]  9   13 [nM] 23   494 [nM] 10  142 [nM] 24    4[nM] 11   53 [nM] 25   418 [nM] 12   27 [nM] 26    6 [nM] 13  486 [nM]27    12 [nM] 14  479 [nM] 28   658 [nM] Example hKi Example hKi 29   4[nM] 43    39 [nM] 30   5 [nM] 44   166 [nM] 31  276 [nM] 45    6 [nM]32  333 [nM] 46   302 [nM] 33  148 [nM] 47    94 [nM] 34   63 [nM] 48   7 [nM] 35   96 [nM] 49    4 [nM] 36   51 [nM] 50    9 [nM] 37   25[nM] 51    8 [nM] 38    6 [nM] 52    1 [nM] 39  287 [nM] 53    2 [nM] 40  26 [nM] 54    28 [nM] 41    3 [nM] 42    8 [nM] Example hKi ExamplehKi 28a   45 [nM] 53a    7 [nM] 28b  0.5 [nM] 53b    20 [nM] 28c  0.4[nM] 53c    98 [nM] 28d   12 [nM] 53d    19 [nM] 28e   20 [nM] 53e    16[nM] 28f   78 [nM] 53f    12 [nM] 28g   8 [nM] 53g    16 [nM] 28h   4[nM] 53h    2 [nM] 28i  221 [nM] 53i    2 [nM] 28j   1 [nM] 53j    21[nM] 28k   3 [nM] 53k    9 [nM] 53l   0.5 [nM] 53m   0.3 [nM] ExamplehKi Example hKi 54a   5 [nM] 53aa    2 [nM] 28l   2 [nM] 53ab    1 [nM]28m   1 [nM] 53ac   0.8 [nM] 28n   38 [nM] 53ad   0.3 [nM] 53n   5 [nM]53ae   0.4 [nM] 53o   1 [nM] 53af    8 [nM] 53p  0.8 [nM] 53ag    5 [nM]53q   1 [nM] 53ah   0.8 [nM] 53r  0.8 [nM] 53af   1.1 [nM] 53s  0.2 [nM]53aj   0.7 [nM] 53t  0.4 [nM] 53ak   0.8 [nM] 53u   3 [nM] 53al   0.4[nM] 53v   7 [nM] 53am   0.3 [nM] 53w  0.6 [nM] 55   311 [nM] 53x   9[nM] 56   802 [nM] 53y   16 [nM] 57  1802 [nM] 53z   3 [nM] 58  1134[nM] 59   263 [nM] 60   733 [nM]

Based on the ability of the substances described by formula (I) toeffectively bind to CCR2 a range of therapeutic applications can beenvisaged. The present invention provides a method for modulating ortreating at least one MCP-1 related disease, in a cell, tissue, organ,animal, or patient, as known in the art or as described herein, using atleast one CCR2 antagonist of the present invention. The presentinvention also provides a method for modulating or treating at least oneMCP-1 related disease, in a cell, tissue, organ, animal, or patientincluding, but not limited to, at least one of malignant disease,metabolic disease, an immune or inflammatory related disease, acardiovascular disease, an infectious disease, or a neurologic disease.Such conditions are selected from, but not limited to, diseases orconditions mediated by cell adhesion and/or angiogenesis. Such diseasesor conditions include an immune disorder or disease, a cardiovasculardisorder or disease, an infectious, malignant, and/or neurologicdisorder or disease, or other known or specified MCP-1 relatedconditions. In particular, the CCR2 antagonists are useful for thetreatment of diseases that involve inflammation such as COPD,angiogenesis such as disease of the eye and neoplastic disease, tissueremodeling such as restenosis, and proliferation of certain cells typesparticularly epithelial and squamous cell carcinomas. Particularindications include use in the treatment of atherosclerosis, restenosis,cancer metastasis, rheumatoid arthritis, diabetic retinopathy andmacular degeneration. The antagonists may also be useful in thetreatment of various fibrotic diseases such as idiopathic pulmonaryfibrosis, diabetic nephropathy, hepatitis, and cirrhosis. Thus, thepresent invention provides a method for modulating or treating at leastone CCR2 related disease, in a cell, tissue, organ, animal, or patient,as known in the art or as described herein, using at least one CCR2antagonist of the present invention. Particular indications arediscussed below:

Pulmonary Diseases

The present invention also provides a method for modulating or treatingat least one malignant disease in a cell, tissue, organ, animal orpatient, including, but not limited to, at least one of: pneumonia; lungabscess; occupational lung diseases caused be agents in the form ordusts, gases, or mists; asthma, bronchiolitis fibrosa obliterans,respiratory failure, hypersensitivity diseases of the lungs includinghypersensitivity pneumonitis (extrinsic allergic alveolitis), allergicbronchopulmonary aspergillosis, and drug reactions; adult respiratorydistress syndrome (ARDS), Goodpasture's Syndrome, chronic obstructiveairway disorders (COPD), idiopathic interstitial lung diseases such asidiopathic pulmonary fibrosis and sarcoidosis, desquamative interstitialpneumonia, acute interstitial pneumonia, respiratorybronchiolitis-associated interstitial lung disease, idiopathicbronchiolitis obliterans with organizing pneumonia, lymphocyticinterstitial pneumonitis, Langerhans' cell granulomatosis, idiopathicpulmonary hemosiderosis; acute bronchitis, pulmonary alveolar,proteinosis, bronchiectasis, pleural disorders, atelectasis, cysticfibrosis, and tumors of the lung, and pulmonary embolism.

Malignant Diseases

The present invention also provides a method for modulating or treatingat least one malignant disease in a cell, tissue, organ, animal orpatient, including, but not limited to, at least one of: leukemia, acuteleukemia, acute lymphoblastic leukemia (ALL), B-cell, T-cell or FAB ALL,acute myeloid leukemia (AML), chromic myelocytic leukemia (CML), chroniclymphocytic leukemia (CLL), hairy cell leukemia, myelodyplastic syndrome(MDS), a lymphoma, Hodgkin's disease, a malignant lymphoma,non-hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, Kaposi'ssarcoma, colorectal carcinoma, pancreatic carcinoma, renal cellcarcinoma, breast cancer, nasopharyngeal carcinoma, malignanthistiocytosis, paraneoplastic syndrome/hypercalcemia of malignancy,solid tumors, adenocarcinomas, squamous cell carcinomas, sarcomas,malignant melanoma, particularly metastatic melanoma, hemangioma,metastatic disease, cancer related bone resorption, cancer related bonepain, and the like.

Immune Related Diseases

The present invention also provides a method for modulating or treatingat least one immune related disease, in a cell, tissue, organ, animal,or patient including, but not limited to, at least one of rheumatoidarthritis, juvenile rheumatoid arthritis, systemic onset juvenilerheumatoid arthritis, psoriatic arthritis, ankylosing spondilitis,gastric ulcer, seronegative arthropathies, osteoarthritis, inflammatorybowel disease, ulcerative colitis, systemic lupus erythematosis,antiphospholipid syndrome, iridocyclitisluveitisloptic neuritis,idiopathic pulmonary fibrosis, systemic vasculitis/wegener'sgranulomatosis, sarcoidosis, orchitislvasectomy reversal procedures,allergiclatopic diseases, asthma, allergic rhinitis, eczema, allergiccontact dermatitis, allergic conjunctivitis, hypersensitivitypneumonitis, transplants, organ transplant rejection, graft-versus-hostdisease, systemic inflammatory response syndrome, sepsis syndrome, grampositive sepsis, gram negative sepsis, culture negative sepsis, fungalsepsis, neutropenic fever, urosepsis, meningococcemia,traumalhemo˜˜hage, bums, ionizing radiation exposure, acutepancreatitis, adult respiratory distress syndrome, rheumatoid arthritis,alcohol-induced hepatitis, chronic inflammatory pathologies,sarcoidosis, Crohn's pathology, sickle cell anemia, diabetes, nephrosis,atopic diseases, hypersensitity reactions, allergic rhinitis, hay fever,perennial rhinitis, conjunctivitis, endometriosis, asthma, urticaria,systemic anaphalaxis, dermatitis, pernicious anemia, hemolytic diseases,thrombocytopenia, graft rejection of any organ or tissue, kidneytransplant rejection, heart transplant rejection, liver transplantrejection, pancreas transplant rejection, lung transplant rejection,bone marrow transplant (BMT) rejection, skin allograft rejection,cartilage transplant rejection, bone graft rejection, small boweltransplant rejection, fetal thymus implant rejection, parathyroidtransplant rejection, xenograft rejection of any organ or tissue,allograft rejection, anti-receptor hypersensitivity reactions, Gravesdisease, Raynoud's disease, type B insulin-resistant diabetes, asthma,myasthenia gravis, antibody-meditated cytotoxicity, type IUhypersensitivity reactions, systemic lupus erythematosus, POEMS syndrome(polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy,and skin changes syndrome), polyneuropathy, organomegaly,endocrinopathy, monoclonal garnrnopathy, skin changes syndrome,antiphospholipid syndrome, pemphigus, scleroderma, mixed connectivetissue disease, idiopathic Addison's disease, diabetes mellitus, chronicactive hepatitis, primary billiary cirrhosis, vitiligo, vasculitis,post-MI cardiotomy syndrome, type IV hypersensitivity, contactdermatitis, hypersensitivity pneumonitis, allograft rejection,granulomas due to intracellular organisms, drug sensitivity,metabolic/idiopathic, Wilson's disease, hemachromatosis,alpha-1-antitrypsin deficiency, diabetic retinopathy, hashimoto'sthyroiditis, osteoporosis, hypothalamic-pituitary-adrenal axisevaluation, primary biliary cirrhosis, thyroiditis, encephalomyelitis,cachexia, cystic fibrosis, neonatal chronic lung disease, chronicobstructive pulmonary disease (COPD), familial hematophagocyticlymphohistiocytosis, dermatologic conditions, psoriasis, alopecia,nephrotic syndrome, nephritis, glomerular nephritis, acute renalfailure, hemodialysis, uremia, toxicity, preeclampsia, OKT3 therapy,anti-CD3 therapy, cytokine therapy, chemotherapy, radiation therapy(e.g., including but not limited toasthenia, anemia, cachexia, and thelike), chronic salicylate intoxication, and the like.

Cardiovascular Diseases

The present invention also provides a method for modulating or treatingat least one cardiovascular disease in a cell, tissue, organ, animal, orpatient, including, but not limited to, at least one of cardiac 25 stunsyndrome, myocardial infarction, congestive heart failure, stroke,ischemic stroke, hemorrhage, arteriosclerosis, atherosclerosis,restenosis, diabetic ateriosclerotic disease, hypertension, arterialhypertension, renovascular hypertension, syncope, shock, syphilis of thecardiovascular system, heart failure, cor pulmonale, primary pulmonaryhypertension, cardiac arrhythmias, atrial ectopic beats, atrial flutter,atrial fibrillation (sustained or paroxysmal), post perfusion syndrome,cardiopulmonary bypass inflammation response, chaotic or multifocalatrial tachycardia, regular narrow QRS tachycardia, specificarrythrnias, ventricular fibrillation, His bundle arrythmias,atrioventricular block, bundle branch block, myocardial ischemicdisorders, coronary artery disease, angina pectoris, myocardialinfarction, cardiomyopathy, dilated congestive cardiomyopathy,restrictive cardiomyopathy, valvular heart diseases, endocarditis,pericardial disease, cardiac tumors, aordic and peripheral aneuryisms,aortic dissection, inflammation of the aorta, occulsion of the abdominalaorta and its branches, peripheral vascular disorders, occulsivearterial disorders, peripheral atherlosclerotic disease, thromboangitisobliterans, functional peripheral arterial disorders, Raynaud'sphenomenon and disease, acrocyanosis, erythromelalgia, venous diseases,venous thrombosis, varicose veins, arteriovenous fistula, lymphederma,lipedema, unstable angina, reperfusion injury, post pump syndrome,ischemia-reperfusion injury, and the like. Such a method can optionallycomprise administering an effective amount of a composition orpharmaceutical composition comprising at least one CCR2 antagonist to acell, tissue, organ, animal or patient in need of such modulation,treatment or therapy.

Neurologic Diseases

The present invention also provides a method for modulating or treatingat least one neurologic disease in a cell, tissue, organ, animal orpatient, including, but not limited to, at least one of: Inflammatorypain, chronic pain, Neuropathic pain such as low back pain, hip pain,leg pain, non-herpetic neuralgia, post herpetic neuralgia, diabeticneuropathy, nerve injury-induced pain, acquired immune deficiencysyndrome (AIDS) related neuropathic pain, head trauma, toxin andchemotherapy caused nerve injuries, phantom limb pain, multiplesclerosis, root avulsions, painful traumatic mononeuropathy, painfulpolyneuropathy, thalamic pain syndrome, post-stroke pain, centralnervous system injury, post surgical pain, carpal tunnel syndrome,trigeminal neuralgia, post mastectomy syndrome, postthoracotomysyndrome, stump pain, repetitive motion pain, neuropathic painassociated hyperalgesia and allodynia, alcoholism and other drug-inducedpain; neurodegenerative diseases, multiple sclerosis, migraine headache,AIDS dementia complex, demyelinating diseases, such as multiplesclerosis and acute transverse myelitis; extrapyramidal and cerebellardisorders' such as lesions of the corticospinal system; disorders of thebasal ganglia or cerebellar disorders; hyperkinetic movement disorderssuch as Huntington's Chorea and senile chorea; drug-induced movementdisorders, such as those induced by drugs which block CNS dopaminereceptors; hypokinetic movement disorders, such as Parkinson's disease;Progressive supra-nucleo Palsy; structural lesions of the cerebellum;spinocerebellar degenerations, such as spinal ataxia, Friedreich'sataxia, cerebellar cortical degenerations, multiple systemsdegenerations (Mencel, Dejerine-Thomas, Shi-Drager, and Machado-Joseph);systemic disorders (Refsum's disease, abetalipoprotemia, ataxia,telangiectasia, and mitochondrial multi.system disorder); demyelinatingcore disorders, such as multiple sclerosis, acute transverse myelitis;and disorders of the motor unit' such as neurogenic muscular atrophies(anterior horn cell degeneration, such as amyotrophic lateral sclerosis,infantile spinal muscular atrophy and juvenile spinal muscular atrophy);Alzheimer's disease; Down's Syndrome in middle age; Diffuse Lewy bodydisease; Senile Dementia of Lewy body type; Wernicke-Korsakoff syndrome;chronic alcoholism; Creutzfeldt-Jakob disease; Subacute sclerosingpanencephalitis, Hallerrorden-Spatz disease; and Dementia pugilistica,and the like.

Fibrotic Conditions

In addition to the above described conditions and diseases, the presentinvention also provides a method for modulating or treating fibroticconditions of various etiologies such as liver fibrosis (including butnot limited to alcohol-induced cirrhosis, viral-induced cirrhosis,autoirnrnune-induced hepatitis); lung fibrosis (including but notlimited to scleroderma, idiopathic pulmonary fibrosis); kidney fibrosis(including but not limited to scleroderma, diabetic nephritis,glomerular pehpritis, lupus nephritis); dermal fibrosis (including butnot limited to scleroderma, hypertrophic and keloid scarring, burns);myelofibrosis; Neurofibromatosis; fibroma; intestinal fibrosis; andfibrotic adhesions resulting from surgical procedures.

The present invention also provides a method for modulating or treatingat least one wound, trauma or tissue injury or chronic conditionresulting from or related thereto, in a cell, tissue, organ, animal orpatient, including, but not limited to, at least one of: bodily injuryor a trauma associated with surgery including thoracic, abdominal,cranial, or oral surgery; or wherein the wound is selected from thegroup consisting of aseptic wounds, contused wounds, incised wounds,lacerated wounds, non-penetrating wounds, open wounds, penetratingwounds, perforating wounds, puncture wounds, septic wounds, infarctionsand subcutaneous wounds; or wherein the wound is selected from the groupconsisting of ischemic ulcers, pressure sores, fistulae, severe bites,thermal bums and donor site wounds; or wherein the wound is an aphthouswound, a traumatic wound or a herpes associated wound. Donor site woundsare wounds which e.g. occur in connection with removal of hard tissuefrom one part of the body to another part of the body e.g. in connectionwith transplantation. The wounds resulting from such operations are verypainful and an improved healing is therefore most valuable. Woundfibrosis is also amenable to CCR2 antagonist therapy as the first cellsto invade the wound area are neutrophils followed by monocytes which areactivated by macrophages. Macrophages are believed to be essential forefficient wound healing in that they also are responsible forphagocytosis of pathogenic organisms and a clearing up of tissue debris.Furthermore, they release numerous factors involved in subsequent eventsof the healing process. The macrophages attract fibroblasts which startthe production of collagen. Almost all tissue repair processes includethe early connective tissue formation, a stimulation of this and thesubsequent processes improve tissue healing, however, overproduction ofconnective tissue and collegen can lead to a fibrotic tissuecharacterized as inelastic and hypoxic. The CCR2 antagonist of theinvention can be used in methods for modulating, treating or preventingsuch sequelae of wound healing.

Other Therapeutic Uses of CCR2 Antagonists

The present invention also provides a method for modulating or treatingat least one infectious disease in a cell, tissue, organ, animal orpatient, including, but not limited to, at least one of: acute orchronic bacterial infection, acute and chronic parasitic or infectiousprocesses, including bacterial, viral and fungal infections, HIVinfection, HIV neuropathy, meningitis, hepatitis (A, B or C, or thelike), septic arthritis, peritonitis, pneumonia, epiglottitis, e. coli0157:h7, hemolytic uremic syndrome/thrombolytic thrombocytopenicpurpura, malaria, dengue hemorrhagic fever, leishmaniasis, leprosy,toxic shock syndrome, streptococcal myositis, gas gangrene,mycobacterium tuberculosis, mycobacterium avium intracellulare,pneumocystis carinii pneumonia, pelvic inflammatory disease,orchitislepidydimitis, legionella, lyme disease, influenza a,epstein-barr virus, vital-associated hemaphagocytic syndrome, vitalencephalitisiaseptic meningitis, and the like.

Any method of the present invention can comprise administering aneffective amount of a composition or pharmaceutical compositioncomprising at least one CCR2 antagonist to a cell, tissue, organ, animalor patient in need of such modulation, treatment or therapy.

Besides being useful for human treatment, these compounds are alsouseful for veterinary treatment of companion animals, exotic animals andfarm animals, including mammals, rodents, and the like.

Combinations

The compounds of formula (I) may be used on their own or in conjunctionwith other active substances of formula (I) according to the invention.If desired the compounds of formula (I) may also be used in combinationwith other pharmacologically active substances. It is preferable to usefor this purpose active substances selected for example from amongβ2-adrenoceptor-agonists (short and lon-acting betamimetics),anti-cholinergics (short and lon-acting), anti-inflammatory steroids(oral and topical corticosteroids), cromoglycate, methylxanthine,dissociated-glucocorticoidmimetics, PDE3 inhibitors, PDE4-inhibitors,PDE7-inhibitors, LTD4 antagonists, EGFR-inhibitors, Dopamine agonists,statins, PAF antagonists, Lipoxin A4 derivatives, FPRL1 modulators,LTB4-receptor (BLT1, BLT2) antagonists, Histamine H1 receptorantagonists, Histamine H4 receptor antagonists, dual HistamineH1/H3-receptor antagonists, PI3-kinase inhibitors, inhibitors ofnon-receptor tyrosine kinases as for example LYN, LCK, SYK (spleentyrosine kinase-inhibitors), ZAP-70, FYN, BTK or ITK, inhibitors of MAPkinases as for example p38, ERK1, ERK2, JNK1, JNK2, JNK3 or SAP,inhibitors of the NF-kappaB signalling pathway as for example IKK2kinase inhibitors, iNOS inhibitors (inducible nitric oxidesynthase-inhibitors), MRP4 inhibitors, leukotriene antagonists,leukotriene biosynthese inhibitors as for example 5-Lipoxygenase (5-LO)inhibitors, cPLA2 inhibitors, Leukotriene A4 Hydrolase inhibitors orFLAP inhibitors, non-steroidal antiinfiammatory drugs (NSAIDs) includingCOX-2 inhibitors, CRTH2 antagonists, DP1-receptor modulators,Thromboxane receptor antagonists, CCR1 antagonists, CCR4 antagonists,CCR5 antagonists, CCR6 antagonists, CCR7 antagonists, CCR8 antagonists,CCR9 antagonists, CCR10 antagonists, CCR11 antagonists, CXCR1antagonists, CXCR2 antagonists, CXCR3 antagonists, CXCR4 antagonists,CXCR5 antagonists, CXCR6 antagonists, CX3CR1 antagonists, Neurokinin(NK1, NK2) antagonists, Sphingosine 1-Phosphate receptor modulators,Sphingosine 1 phosphate lyase inhibitors, Adenosine receptor modulatorsas for example A2a-agonists, modulators of purinergic rezeptors as forexample P2X7 inhibitors, Histone Deacetylase (HDAC) activators,Bradykinin (BK1, BK2) antagonists, TACE inhibitors, PPAR gammamodulators, Rho-kinase inhibitors, interleukin 1-beta converting enzyme(ICE) inhibitors, Toll-Like receptor (TLR) modulators, HMG-CoA reductaseinhibitors, VLA-4 antagonists, ICAM-1 inhibitors, SHIP agonists, GABAareceptor antagonist, ENaC-inhibitors, Melanocortin receptor (MC1R, MC2R,MC3R, MC4R, MC5R) modulators, CGRP antagonists, Endothelin antagonists,TNFalpha antagonists, anti-TNF antibodies, anti-GM-CSF antibodies,anti-CD46 antibodies, anti-IL-1 antibodies, anti-IL-2 antibodies,anti-IL-4 antibodies, anti-IL-5 antibodies, anti-IL-13 antibodies,anti-IL-4/IL-13 antibodies, anti-TSLP antibodies, anti-OX40 antibodies,mucoregulators, immunotherapeutic agents, compounds against swelling ofthe airways, compounds against cough, antiviral drugs, opiate receptoragonists, cannabionoid agonists, sodium channel blockers, N-type calciumchannel blockers, serotonergic and noradrenergic modulators, proton pumpinhibitors, local anesthetics, VR1 agonists and antagonists, Nicotinicacetylcholine receptor agonists, P2X3 receptor antagonists, NGF agonistsand antagonists, NMDA antagonist, potassium channel modulators, GABAmodulators, serotonergic and noradrenergic modulators, anti-migrainedrugs. The invention also encompasses combinations of three activesubstances, each selected from one of the above-mentioned categories ofcompounds. Said list is not considered to have a limiting character.

The betamimetics used are preferably compounds selected from amongalbuterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol,fenoterol, formoterol, arformoterol, zinterol, hexoprenaline, ibuterol,isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine,metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol,rimiterol, ritodrine, salmeterol, salmefamol, soterenol, sulphonterol,tiaramide, terbutaline, tolubuterol, CHF-1035, HOKU-81, KUL-1248,3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzyl-sulphonamide,5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one,4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone,1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one,1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol,6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetateethyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-aceticacid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyricacid,8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneand1-(4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol,optionally in the form of the racemates, enantiomers, diastereomersthereof and optionally in the form of the pharmacologically acceptableacid addition salts, solvates or hydrates thereof.

Preferably the beta mimetics are selected from among bambuterol,bitolterol, carbuterol, clenbuterol, fenoterol, formoterol,hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, salmeterol,sulphonterol, terbutaline, tolubuterol,3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulphonamide,5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one,4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone,1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one,1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol,6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetateethyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-aceticacid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl]-6-hydroxy-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1.1dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyricacid,8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneand1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol,optionally in the form of the racemates, enantiomers, diastereomersthereof and optionally in the form of the pharmacologically acceptableacid addition salts, solvates or hydrates thereof.

Particularly preferred betamimetics are selected from among fenoterol,formoterol, salmeterol,3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulphonamide,5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one,1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetateethyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-aceticacid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1.1dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyricacid,8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneand1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,optionally in the form of the racemates, enantiomers, diastereomersthereof and optionally in the form of the pharmacologically acceptableacid addition salts, solvates or hydrates thereof.

Of these betamimetics those which are particularly preferred accordingto the invention are formoterol, salmeterol,3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulphonamide,6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(ethyl4-phenoxy-acetate)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-aceticacid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1.1dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyricacid,8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneand5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one,optionally in the form of the racemates, enantiomers, diastereomersthereof and optionally in the form of the pharmacologically acceptableacid addition salts, solvates or hydrates thereof.

According to the invention the acid addition salts of the betamimeticsare preferably selected from among hydrochloride, hydrobromide,hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate,hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate,hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoateand hydro-p-toluenesulphonat, preferably hydrochloride, hydrobromide,hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.Of the above-mentioned acid addition salts the salts of hydrochloricacid, methanesulphonic acid, benzoic acid and acetic acid areparticularly preferred according to the invention.

The anticholinergics used are preferably compounds selected from amongthe tiotropium salts, oxitropium salts, flutropium salts, ipratropiumsalts, glycopyrronium salts, trospium salts, tropenol2,2-diphenylpropionate methobromide, scopine 2,2-diphenylpropionatemethobromide, scopine 2-fluoro-2,2-diphenylacetate methobromide,tropenol 2-fluoro-2,2-diphenylacetate methobromide, tropenol3,3′,4,4′-tetrafluorobenzilate methobromide, scopine3,3′,4,4′-tetrafluorobenzilate methobromide, tropenol4,4′-difluorobenzilate methobromide, scopine 4,4′-difluorobenzilatemethobromide, tropenol 3,3′-difluorobenzilate methobromide, -scopine3,3′-difluorobenzilate methobromide, tropenol9-hydroxy-fluorene-9-carboxylate-methobromide, tropenol9-fluoro-fluorene-9-carboxylate-methobromide, scopine9-hydroxy-fluoren-9-carboxylate methobromide, scopine9-fluoro-fluorene-9-carboxylate methobromide, tropenol9-methyl-fluorene-9-carboxylate methobromide, scopine9-methyl-fluorene-9-carboxylate methobromide, cyclopropyltropinebenzilate methobromide, cyclopropyltropine 2,2-diphenylpropionatemethobromide, cyclopropyltropine 9-hydroxy-xanthene-9-carboxylatemethobromide, cyclopropyltropine 9-methyl-fluorene-9-carboxylatemethobromide, cyclopropyltropine 9-methyl-xanthene-9-carboxylatemethobromide, cyclopropyltropine 9-hydroxy-fluorene-9-carboxylatemethobromide, methyl-cyclopropyltropine 4,4′-difluorobenzilatemethobromide, tropenol 9-hydroxy-xanthene-9-carboxylate-methobromide,scopine 9-hydroxy-xanthene-9-carboxylate methobromide, tropenol9-methyl-xanthene-9-carboxylate methobromide, scopine9-methyl-xanthene-9-carboxylate methobromide, tropenol9-ethyl-xanthene-9-carboxylate methobromide, tropenol9-difluoromethyl-xanthene-9-carboxylate methobromide, scopine9-hydroxymethyl-xanthene-9-carboxylate methobromide, optionally in theform of the solvates or hydrates thereof. In the above-mentioned saltsthe cations tiotropium, oxitropium, flutropium, ipratropium,glycopyrronium and trospium are the pharmacologically activeingredients. As anions, the above-mentioned salts may preferably containchloride, bromide, iodide, sulphate, phosphate, methanesulphonate,nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate,succinate, benzoate or p-toluenesulphonate, while chloride, bromide,iodide, sulphate, methanesulphonate or p-toluenesulphonate are preferredas counter-ions. Of all the salts, the chlorides, bromides, iodides andmethanesulphonate are particularly preferred. Of particular importanceis tiotropium bromide. In the case of tiotropium bromide thepharmaceutical combinations according to the invention preferablycontain it in the form of the crystalline tiotropium bromidemonohydrate, which is known from WO 02/30928. If the tiotropium bromideis used in anhydrous form in the pharmaceutical combinations accordingto the invention, it is preferable to use anhydrous crystallinetiotropium bromide, which is known from WO 03/000265.

Corticosteroids used here are preferably compounds selected from amongprednisolone, prednisone, butixocortpropionate, flunisolide,beclomethasone, triamcinolone, budesonide, fluticasone, mometasone,ciclesonide, rofleponide, dexamethasone, betamethasone, deflazacort,RPR-106541, NS-126, (S)-fluoromethyl6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionateand (S)-(2-oxo-tetrahydro-furan-3S-yl)6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionate,optionally in the form of the racemates, enantiomers or diastereomersthereof and optionally in the form of the salts and derivatives,solvates and/or hydrates thereof.

Particularly preferred is the steroid selected from among flunisolide,beclomethasone, triamcinolone, budesonide, fluticasone, mometasone,ciclesonide, rofleponide, dexamethasone, NS-126, (S)-fluoromethyl6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionateand (S)-(2-oxo-tetrahydro-furan-3S-yl)6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionate,optionally in the form of the racemates, enantiomers or diastereomersthereof and optionally in the form of the salts and derivatives,solvates and/or hydrates thereof.

Particularly preferred is the steroid selected from among budesonide,fluticasone, mometasone, ciclesonide and (S)-fluoromethyl6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate,optionally in the form of the racemates, enantiomers or diastereomersthereof and optionally in the form of the salts and derivatives,solvates and/or hydrates thereof.

Any reference to steroids includes a reference to any salts orderivatives, hydrates or solvates thereof which may exist. Examples ofpossible salts and derivatives of the steroids may be: alkali metalsalts, such as for example sodium or potassium salts, sulphobenzoates,phosphates, isonicotinates, acetates, propionates, dihydrogenphosphates, palmitates, pivalates or furoates thereof.

PDE4 inhibitors which may be used are preferably compounds selected fromamong enprofyllin, theophyllin, roflumilast, ariflo (cilomilast),tofimilast, pumafentrin, lirimilast, arofyllin, atizoram, D-4396(Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418,PD-168787, T-440, T-2585, V-11294A, C1-1018, CDC-801, CDC-3052, D-22888,YM-58997, Z-15370,N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide,(−)p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide,(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone,3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N-2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone,cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid],2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-one,cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol],(R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate,(S)-(−)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate,9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridineand9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine,optionally in the form of the racemates, enantiomers or diastereomersand optionally in the form of the pharmacologically acceptable acidaddition salts, solvates and/or hydrates thereof.

The PDE4-inhibitor used are preferably compounds selected from amongenprofyllin, roflumilast, ariflo (cilomilast), arofyllin, atizoram,AWD-12-281 (GW-842470), T-440, T-2585, PD-168787, V-11294A, C1-1018,CDC-801, D-22888, YM-58997, Z-15370,N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide,cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid],2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one,cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol],9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridineand9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine,optionally in the form of the racemates, enantiomers or diastereomersand optionally in the form of the pharmacologically acceptable acidaddition salts, solvates and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which theabove-mentioned PDE4-inhibitors might be in a position to form aremeant, for example, salts selected from among the hydrochloride,hydrobromide, hydroiodide, hydrosulphate, hydrophosphate,hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferablyhydrochloride, hydrobromide, hydrosulphate, hydrophosphate,hydrofumarate and hydromethanesulphonate.

LTD4-antagonists which may be used are preferably compounds selectedfrom among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523),MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321,1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-aceticacid,1-(((1(R)-3(3-(2-(2.3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane-aceticacid and[2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]aceticacid, optionally in the form of the racemates, enantiomers ordiastereomers, optionally in the form of the pharmacologicallyacceptable acid addition salts and optionally in the form of the saltsand derivatives, solvates and/or hydrates thereof.

Preferably the LTD4-antagonist is selected from among montelukast,pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507),VUF-5078, VUF-K-8707 and L-733321, optionally in the form of theracemates, enantiomers or diastereomers, optionally in the form of thepharmacologically acceptable acid addition salts and optionally in theform of the salts and derivatives, solvates and/or hydrates thereof.

Particularly preferably the LTD4-antagonist is selected from amongmontelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001 andMEN-91507 (LM-1507), optionally in the form of the racemates,enantiomers or diastereomers, optionally in the form of thepharmacologically acceptable acid addition salts and optionally in theform of the salts and derivatives, solvates and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which theLTD4-antagonists may be capable of forming are meant, for example, saltsselected from among the hydrochloride, hydrobromide, hydroiodide,hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate,hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide,hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.By salts or derivatives which the LTD4-antagonists may be capable offorming are meant, for example: alkali metal salts, such as, forexample, sodium or potassium salts, alkaline earth metal salts,sulphobenzoates, phosphates, isonicotinates, acetates, propionates,dihydrogen phosphates, palmitates, pivalates or furoates.

EGFR-inhibitors which may be used are preferably compounds selected fromamong4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxyl-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin,3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline,4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{[4-(5.5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2.6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxyl-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline,Cetuximab, Trastuzumab, ABX-EGF and Mab ICR-62, optionally in the formof the racemates, enantiomers or diastereomers thereof, optionally inthe form of the pharmacologically acceptable acid addition salts, thesolvates and/or hydrates thereof.

Preferred EGFR inhibitors are selected from among4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine,3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline,4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{[4-(5.5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2.6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxyl-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline,and Cetuximab, optionally in the form of the racemates, enantiomers ordiastereomers thereof, optionally in the form of the pharmacologicallyacceptable acid addition salts, the solvates and/or hydrates thereof.

Preferable the EGFR-inhibitors are selected from among4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine,3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{[4-(5.5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline,and4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,optionally in the form of the racemates, enantiomers or diastereomersthereof, optionally in the form of the pharmacologically acceptable acidaddition salts, the solvates and/or hydrates thereof.

EGFR-inhibitors are preferably selected from among4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{[4-(5.5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazolineand4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazolineoptionally in the form of the racemates, enantiomers or diastereomersthereof, optionally in the form of the pharmacologically acceptable acidaddition salts, the solvates and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which theEGFR-inhibitors may be capable of forming are meant, for example, saltsselected from among the hydrochloride, hydrobromide, hydroiodide,hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate,hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide,hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.

Examples of dopamine agonists which may be used preferably includecompounds selected from among bromocriptine, cabergoline,alpha-dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol,ropinirol, talipexol, terguride and viozan. Any reference to theabove-mentioned dopamine agonists within the scope of the presentinvention includes a reference to any pharmacologically acceptable acidaddition salts and optionally hydrates thereof which may exist. By thephysiologically acceptable acid addition salts which may be formed bythe above-mentioned dopamine agonists are meant, for example,pharmaceutically acceptable salts which are selected from the salts ofhydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lacticacid, citric acid, tartaric acid and maleic acid.

Examples of H1-antihistamines preferably include compounds selected fromamong epinastine, cetirizine, azelastine, fexofenadine, levocabastine,loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine,bamipin, cexchlorpheniramine, pheniramine, doxylamine,chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine,ebastine, desloratidine and meclozine. Any reference to theabove-mentioned H1-antihistamines within the scope of the presentinvention includes a reference to any pharmacologically acceptable acidaddition salts which may exist.

Examples of PAF-antagonists preferably include compounds selected fromamong4-(2-chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-1-yl]-6H-thieno-[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepines,6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclo-penta-[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepines.

MRP4-inhibitors used are preferably compounds selected from amongN-acetyl-dinitrophenyl-cysteine, cGMP, cholate, diclofenac,dehydroepiandrosterone 3-glucuronide, dehydroepiandrosterone 3-sulphate,dilazep, dinitrophenyl-s-glutathione, estradiol 17-β-glucuronide,estradiol 3,17-disulphate, estradiol 3-glucuronide, estradiol3-sulphate, estrone 3-sulphate, flurbiprofen, folate,N5-formyl-tetrahydrofolate, glycocholate, clycolithocholic acidsulphate, ibuprofen, indomethacin, indoprofen, ketoprofen, lithocholicacid sulphate, methotrexate, MK571((E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-[[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoicacid), α-naphthyl-β-D-glucuronide, nitrobenzyl mercaptopurine riboside,probenecid, PSC833, sildenafil, sulfinpyrazone, taurochenodeoxycholate,taurocholate, taurodeoxycholate, taurolithocholate, taurolithocholicacid sulphate, topotecan, trequinsin and zaprinast, dipyridamole,optionally in the form of the racemates, enantiomers, diastereomers andthe pharmacologically acceptable acid addition salts and hydratesthereof. MRP4-inhibitors are preferably selected from amongN-acetyl-dinitrophenyl-cysteine, dehydroepiandrosterone 3-sulphate,dilazep, dinitrophenyl-S-glutathione, estradiol 3,17-disulphate,flurbiprofen, glycocholate, glycolithocholic acid sulphate, ibuprofen,indomethacin, indoprofen, lithocholic acid sulphate, MK571, PSC833,sildenafil, taurochenodeoxycholate, taurocholate, taurolithocholate,taurolithocholic acid sulphate, trequinsin and zaprinast, dipyridamole,optionally in the form of the racemates, enantiomers, diastereomers andthe pharmacologically acceptable acid addition salts and hydratesthereof. Particularly preferred MRP4-inhibitors are selected from amongdehydroepiandrosterone 3-sulphate, estradiol 3,17-disulphate,flurbiprofen, indomethacin, indoprofen, MK571, taurocholate, optionallyin the form of the racemates, enantiomers, diastereomers and thepharmacologically acceptable acid addition salts and hydrates thereof.The separation of enantiomers from the racemates can be carried outusing methods known from the art (e.g. chromatography on chiral phases,etc.).

By acid addition salts with pharmacologically acceptable acids aremeant, for example, salts selected from among the hydrochlorides,hydrobromides, hydroiodides, hydrosulphates, hydrophosphates,hydromethanesulphonates, hydronitrates, hydromaleates, hydroacetates,hydrobenzoates, hydrocitrates, hydrofumarates, hydrotartrates,hydrooxalates, hydrosuccinates, hydrobenzoates andhydro-p-toluenesulphonates, preferably the hydrochlorides,hydrobromides, hydrosulphates, hydrophosphates, hydrofumarates andhydromethanesulphonates.

The invention further relates to pharmaceutical preparations whichcontain a triple combination of the CCR2 inhibitors, MRP4-inhibitors andanother active substance according to the invention, such as, forexample, an anticholinergic, a steroid, an LTD4-antagonist or abetamimetic, and the preparation thereof and the use thereof fortreating respiratory complaints.

The iNOS-inhibitors used are preferably compounds selected from among:S-(2-aminoethyl)isothiourea, aminoguanidine, 2-aminomethylpyridine, AMT,L-canavanine, 2-iminopiperidine, S-isopropylisothiourea,S-methylisothiourea, S-ethylisothiourea, S-methyltiocitrulline,S-ethylthiocitrulline, L-NA (N^(ω)-nitro-L-arginine), L-NAME(N^(ω)-nitro-L-arginine methylester), L-NMMA(N^(G)-monomethyl-L-arginine), L-NIO (N^(ω)-iminoethyl-L-ornithine),L-NIL (N^(ω)-iminoethyl-lysine), (S)-6-acetimidoylamino-2-amino-hexanoicacid (1H-tetrazol-5-yl)-amide (SC-51) (J. Med. Chem. 2002, 45,1686-1689), 1400W,(S)-4-(2-acetimidoylamino-ethylsulphanyl)-2-amino-butyric acid(GW274150) (Bioorg. Med. Chem. Lett. 2000, 10, 597-600),2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine(BYK191023) (Mol. Pharmacol. 2006, 69, 328-337),2-((R)-3-amino-1-phenyl-propoxy)-4-chloro-5-fluorobenzonitrile (WO01/62704),2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-6-trifluoromethyl-nicotinonitrile(WO 2004/041794),2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-4-chloro-benzonitrile(WO 2004/041794),2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-5-chloro-benzonitrile(WO 2004/041794),(2S,4R)-2-amino-4-(2-chloro-5-trifluoromethyl-phenylsulphanyl)-4-thiazol-5-yl-butan-1-ol(WO 2004/041794),2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-5-chloro-nicotinonitrile(WO 2004/041794),4-((S)-3-amino-4-hydroxy-1-phenyl-butylsulphanyl)-6-methoxy-nicotinonitrile(WO 02/090332), substituted 3-phenyl-3,4-dihydro-1-isoquinolinaminessuch as e.g. AR-C102222 (J. Med. Chem. 2003, 46, 913-916),(1S.5S.6R)-7-chloro-5-methyl-2-aza-bicyclo[4.1.0]hept-2-en-3-ylamine(ONO-1714) (Biochem. Biophys. Res. Commun. 2000, 270, 663-667),(4R.5R)-5-ethyl-4-methyl-thiazolidin-2-ylideneamine (Bioorg. Med. Chem.2004, 12, 4101), (4R.5R)-5-ethyl-4-methyl-selenazolidin-2-ylideneamine(Bioorg. Med. Chem. Lett. 2005, 15, 1361), 4-aminotetrahydrobiopterine(Curr. Drug Metabol. 2002, 3, 119-121),(E)-3-(4-chloro-phenyl)-N-(1-2-oxo-2-{4-(6-trifluoromethyl-pyrimidin-4-yloxy)-piperidin-1-yl]-ethylcarbamoyl}-2-pyridin-2-yl-ethyl)-acrylamide(FR260330) (Eur. J. Pharmacol. 2005, 509, 71-76),3-(2,4-difluoro-phenyl)-6-[2-(4-imidazol-1-ylmethyl-phenoxy)-ethoxy]-2-phenyl-pyridine(PPA250) (J. Pharmacol. Exp. Ther. 2002, 303, 52-57), methyl3-{[(benzo[1.3]dioxol-5-ylmethyl)-carbamoyl]-methyl}-4-(2-imidazol-1-yl-pyrimidin-4-yl)-piperazin-1-carboxylate(BBS-1) (Drugs Future 2004, 29, 45-52),(R)-1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidine-2-carboxylicacid (2-benzo[1.3]dioxol-5-yl-ethyl)-amide (BBS-2) (Drugs Future 2004,29, 45-52) and the pharmaceutical salts, prodrugs or solvates thereof.

Compounds which may be used as SYK-inhibitors are preferably compoundsselected from among: R343 or R788.

Examples of preferred MAP kinase inhibitors, as for example p38, ERK1,ERK2, JNK1, JNK2, JNK3 or SAP, which may be mentioned include SCIO-323,SX-011, SD-282, SD-169, NPC-037282, SX-004, VX-702, GSK-681323,GSK-856553, ARRY-614, ARRY-797, ARRY-438162, ARRY-p38-002, ARRY-371797,AS-602801, AS-601245, AS-602183, CEP-1347, KC706, TA-5493, RO-6226,Ro-1487, SC-409, CBS-3595, VGX-1027, PH-797804, BMS-582949, TA-5493 andBIRB-796 optionally in racemic form, as enantiomers, diastereomeres oras pharmacologically acceptable salts, solvates or hydrates.

Examples of preferred inhibitors of the NF-κB signaling pathwayincluding IKK2 kinase inhibitors which may be mentioned include:MD-1041, MLN-041 and AVE-0547 optionally in racemic form, asenantiomers, diastereomeres or as pharmacologically acceptable salts,solvates or hydrates.

Examples of preferred Leukotriene biosynthesis inhibitors, as forexample 5-Lipoxygenase (5-LO) inhibitors, cPLA2 inhibitors, LeukotrieneA4 hydrolase inhibitors oder FLAP inhibitors, which may be mentionedinclude zileuton, tipelukast, licofelone, darapladib, TA-270, IDEA-033,IDEA-070, NIK-639, ABT-761, fenleuton, tepoxalin, AM-103, AM-803,Abbott-79175, Abbott-85761, PLT-3514, CMI-903, PEP-03, CMI-977, MLN-977,CMI-947, LDP-977, efipladib, PLA-695, veliflapon, MK-591, MK-886 undBAYx1005 optionally in racemic form, as enantiomers, diastereomeres oras pharmacologically acceptable salts, solvates or hydrates.

Examples of preferred non-steroidal anti-inflammatory agents (NSAIDs)which may be mentioned include COX-2 inhibitors :propionic acidderivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen,fenhufen, fenoprofen, flubiprofen, ibuprofen, indoprofen, ketoprofen,miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen,tiaprofenic acid, and tioxaprofen), acetic acid derivatives(indomethacin, acemetacin, alclofenac, clidanac, diclofenac,fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac,oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac),fenamic acid derivatives (meclofenamic acid, mefenamic acid, andtolfenamic acid), biphenyl-carboxylic acid derivatives, oxicams(isoxicam, meloxicam, piroxicam, sudoxicam and tenoxican), salicylates(acetyl salicylic acid, sulfasalazine) and the pyrazolones (apazone,bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone),and the coxibs (celecoxib, valecoxib, rofecoxib and etoricoxib)optionally in racemic form, as enantiomers, diastereomeres or aspharmacologically acceptable salts, solvates or hydrates.

Examples of preferred CCR1 antagonists which may be mentioned includeAZD-4818, CCX-354, MLN-3701, MLN-3897, optionally in racemic form, asenantiomers, diastereomeres or as pharmacologically acceptable salts,solvates or hydrates.

Examples of preferred CCR5 antagonists which may be mentioned includemaraviroc, INCB-15050. CCR5mAb004, GSK-706769, PRO-140, SCH-532706,vicriviroc and nifeviroc optionally in racemic form, as enantiomers,diastereomeres or as pharmacologically acceptable salts, solvates orhydrates.

Examples of preferred CXCR1 or CXCR2 antagonists which may be mentionedinclude SCH-527123 and SB-656933 optionally in racemic form, asenantiomers, diastereomeres or as pharmacologically acceptable salts,solvates or hydrates.

Examples of preferred Neurokinin (NK1 or NK2) antagonists which may bementioned include Saredutant, Nepadutant, PRX-96026 and Figopitantoptionally in racemic form, as enantiomers, diastereomeres or aspharmacologically acceptable salts, solvates or hydrates.

Examples of preferred purinergic receptor modulators, including P2X7inhibitors, which may be mentioned include AZD-9056 optionally inracemic form, as enantiomers, diastereomeres or as pharmacologicallyacceptable salts, solvates or hydrates.

Examples of preferred PPAR gamma modulators which may be mentionedinclude Rosiglitazone, Ciglitazone, Pioglitazone and SMP-028 optionallyin racemic form, as enantiomers, diastereomeres or as pharmacologicallyacceptable salts, solvates or hydrates.

Examples of preferred Interleukin 1-beta converting enzyme (ICE)inhibitors which may be mentioned include Pralnacasan, VRT-18858,RU-36384, VX-765 and VRT-43198 optionally in racemic form, asenantiomers, diastereomeres or as pharmacologically acceptable salts,solvates or hydrates.

Examples of preferred Toll-like receptor (TLR) modulators which may bementioned include Resiquimod, PF-3512676, AVE-0675, Heplisav, IMO-2055,CpG-28, TAK-242, SAR-21609, RC-52743198 and 852A optionally in racemicform, as enantiomers, diastereomeres or as pharmacologically acceptablesalts, solvates or hydrates.

Examples of preferred VLA4 antagonists which may be mentioned includeNatalizumab, Valategrast, TBC-4746, CDP-323 and TL-1102 optionally inracemic form, as enantiomers, diastereomeres or as pharmacologicallyacceptable salts, solvates or hydrates.

Examples of preferred ICAM-1 inhibitors which may be mentioned includeBIRT-2584 optionally in racemic form, as enantiomers, diastereomeres oras pharmacologically acceptable salts, solvates or hydrates.

Examples of preferred anti-TNF antibodies which may be mentioned includeInfliximab, Adalimumab, Golimumab. CytoFab and Etanercept.

Examples of preferred mucoregulators which may be mentioned includeMSI-2216, Erdosteine, Fluorovent, Talniflumate, INO-4995, BIO-11006,VR-496 and fudosteine optionally in racemic form, as enantiomers,diastereomeres or as pharmacologically acceptable salts, solvates orhydrates.

Examples of preferred Antiviral drugs which may be mentioned includeacyclovir, tenovir, pleconaril, peramivir, pocosanol.

Examples of preferred Antibiotic drugs like gentamicin, streptomycin,geldanamycin, doripenem, cephalexin, cefaclor, ceftazichine, cefepime,erythromycin, vancomycin, aztreonam, amoxicillin, bacitracin, enoxacin,mafenide, doxycycline, chloramphenicol.

Examples of preferred opiate receptor agonists are selected from amongmorphine, propoxyphene (Darvon), tramadol, buprenorphin.

Examples of preferred anti-TNF antibodies or TNF-receptor antagonistssuch as but not limited to Etanercept, Infliximab, Adalimumab (D2E7),CDP 571, and Ro 45-2081 (Lenercept), or biologic agents directed againsttargets such as but not limited to CD-4, CTLA-4, LFA-1, IL-6, ICAM-1, C5and Natalizumab.

Examples of preferred IL-1 receptor antagonists such as but not limitedto Kineret; Sodium channel blockers: carbamazepine, mexiletine,lamotrigine, tectin, lacosamide

Examples of preferred N-type calcium channel blockers are selected fromamong Ziconotide.

Examples of preferred Serotonergic and noradrenergic modulators such asbut not limited to paroxetine, duloxetine, clonidine, amitriptyline,citalopram;

Examples of preferred Histamine H1 receptor antagonists such as but notlimited to bromophtniramint, chlorpheniramine, dexchlorpheniramine,triprolidine, clemastine, diphenhydramine, diphenylpyraline,tripelennamine, hydroxyzine, methdiJazine, promethazine, trimeprazine,azatadine, cyproheptadine, antazoline, pheniramine pyrilamine,astemizole, terfenadine, loratadine, cetirizine, deslo-ratadine,fexofenadine and levocetirizine.

Examples of preferred Histamine H2 receptor antagonists such as but notlimited to cimetidine, famotidine and ranitidine.

Examples of preferred proton pump inhibitors such as but not limited toomeprazole, pantoprazole and esomeprazole.

Examples of preferred Leukotriene antagonists and 5-lipoxygenaseinhibitors such as but not limited to zafirlukast, mon-telukast,pranlukast and zileuton.

Examples of preferred local anesthetics such as but not limited toambroxol, lidocaine.

Examples of preferred potassium channel modulators such as but notlimited to retigabine.

Examples of preferred GABA modulators such as but not limited tolacosamide, pregabalin, gabapentin.

Examples of preferred anti-migraine drugs such as but not limited tosumatriptan, zolmitriptan, naratriptan, eletriptan, telcegepant.

Examples of preferred NGF antibodies such as but not limited to RI-724.

Combination therapy is also possible with new principles for thetreatment of pain e.g. P2X3 antagonists, VR1 antagonists, NK1 and NK2antagonists, NMDA antagonists, mGluR antagonists and the like.

Pharmaceutical Formulations

Suitable forms for administration are for example tablets, capsules,solutions, syrups, emulsions or inhalable powders or aerosols. Thecontent of the pharmaceutically effective compound(s) in each caseshould be in the range from 0.1 to 90 wt. %, preferably 0.5 to 50 wt. %of the total composition, i.e. in amounts which are sufficient toachieve the dosage range specified hereinafter.

The preparations may be administered orally in the form of a tablet, asa powder, as a powder in a capsule (e.g. a hard gelatine capsule), as asolution or suspension. When administered by inhalation the activesubstance combination may be given as a powder, as an aqueous oraqueous-ethanolic solution or using a propellant gas formulation.

Preferably, therefore, pharmaceutical formulations are characterised inthat they contain one or more compounds of formula (I) according to thepreferred embodiments above.

It is particularly preferable if the compounds of formula (I) areadministered orally, and it is also particularly preferable if they areadministered once or twice a day. Suitable tablets may be obtained, forexample, by mixing the active substance(s) with known excipients, forexample inert diluents such as calcium carbonate, calcium phosphate orlactose, disintegrants such as corn starch or alginic acid, binders suchas starch or gelatine, lubricants such as magnesium stearate or talcand/or agents for delaying release, such as carboxymethyl cellulose,cellulose acetate phthalate, or polyvinyl acetate. The tablets may alsocomprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups containing the active substances or combinations thereofaccording to the invention may additionally contain a sweetener such assaccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. aflavouring such as vanillin or orange extract. They may also containsuspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers(e.g. lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

For oral administration the tablets may, of course, contain, apart fromthe abovementioned carriers, additives such as sodium citrate, calciumcarbonate and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulphate and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions the active substances may be combined with variousflavour enhancers or colourings in addition to the excipients mentionedabove.

It is also preferred if the compounds of formula (I) are administered byinhalation, particularly preferably if they are administered once ortwice a day. For this purpose, the compounds of formula (I) have to bemade available in forms suitable for inhalation. Inhalable preparationsinclude inhalable powders, propellant-containing metered-dose aerosolsor propellant-free inhalable solutions, which are optionally present inadmixture with conventional physiologically acceptable excipients.

Within the scope of the present invention, the term propellant-freeinhalable solutions also includes concentrates or sterile ready-to-useinhalable solutions. The preparations which may be used according to theinvention are described in more detail in the next part of thespecification.

Inhalable Powders

If the active substances of formula (I) are present in admixture withphysiologically acceptable excipients, the following physiologicallyacceptable excipients may be used to prepare the inhalable powdersaccording to the invention: monosaccharides (e.g. glucose or arabinose),disaccharides (e.g. lactose, saccharose, maltose), oligo- andpolysaccharides (e.g. dextran), polyalcohols (e.g. sorbitol, mannitol,xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures ofthese excipients with one another. Preferably, mono- or disaccharidesare used, while the use of lactose or glucose is preferred,particularly, but not exclusively, in the form of their hydrates. Forthe purposes of the invention, lactose is the particularly preferredexcipient, while lactose monohydrate is most particularly preferred.Methods of preparing the inhalable powders according to the invention bygrinding and micronising and by finally mixing the components togetherare known from the prior art.

Propellant-Containing Inhalable Aerosols

The propellant-containing inhalable aerosols which may be used accordingto the invention may contain the active substances of formula (I)dissolved in the propellant gas or in dispersed form. The propellantgases which may be used to prepare the inhalation aerosols according tothe invention are known from the prior art. Suitable propellant gasesare selected from among hydrocarbons such as n-propane, n-butane orisobutane and halohydrocarbons such as preferably fluorinatedderivatives of methane, ethane, propane, butane, cyclopropane orcyclobutane. The propellant gases mentioned above may be used on theirown or in mixtures thereof. Particularly preferred propellant gases arefluorinated alkane derivatives selected from TG134a(1,1,1,2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3-heptafluoropropane)and mixtures thereof. The propellant-driven inhalation aerosols usedwithin the scope of the use according to the invention may also containother ingredients such as co-solvents, stabilisers, surfactants,antioxidants, lubricants and pH adjusters. All these ingredients areknown in the art.

Propellant-Free Inhalable Solutions

The compounds of formula (I) according to the invention are preferablyused to prepare propellant-free inhalable solutions and inhalablesuspensions. Solvents used for this purpose include aqueous oralcoholic, preferably ethanolic solutions. The solvent may be water onits own or a mixture of water and ethanol. The solutions or suspensionsare adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids.The pH may be adjusted using acids selected from inorganic or organicacids. Examples of particularly suitable inorganic acids includehydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/orphosphoric acid. Examples of particularly suitable organic acids includeascorbic acid, citric acid, malic acid, tartaric acid, maleic acid,succinic acid, fumaric acid, acetic acid, formic acid and/or propionicacid etc. Preferred inorganic acids are hydrochloric and sulphuricacids. It is also possible to use the acids which have already formed anacid addition salt with one of the active substances. Of the organicacids, ascorbic acid, fumaric acid and citric acid are preferred. Ifdesired, mixtures of the above acids may also be used, particularly inthe case of acids which have other properties in addition to theiracidifying qualities, e.g. as flavourings, antioxidants or complexingagents, such as citric acid or ascorbic acid, for example. According tothe invention, it is particularly preferred to use hydrochloric acid toadjust the pH. Co-solvents and/or other excipients may be added to thepropellant-free inhalable solutions used for the purpose according tothe invention. Preferred co-solvents are those which contain hydroxylgroups or other polar groups, e.g. alcohols—particularly isopropylalcohol, glycols—particularly propyleneglycol, polyethyleneglycol,polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols andpolyoxyethylene fatty acid esters. The terms excipients and additives inthis context denote any pharmacologically acceptable substance which isnot an active substance but which can be formulated with the activesubstance or substances in the pharmacologically suitable solvent inorder to improve the qualitative properties of the active substanceformulation. Preferably, these substances have no pharmacological effector, in connection with the desired therapy, no appreciable or at leastno undesirable pharmacological effect. The excipients and additivesinclude, for example, surfactants such as soya lecithin, oleic acid,sorbitan esters, such as polysorbates, polyvinylpyrrolidone, otherstabilisers, complexing agents, antioxidants and/or preservatives whichguarantee or prolong the shelf life of the finished pharmaceuticalformulation, flavourings, vitamins and/or other additives known in theart. The additives also include pharmacologically acceptable salts suchas sodium chloride as isotonic agents. The preferred excipients includeantioxidants such as ascorbic acid, for example, provided that it hasnot already been used to adjust the pH, vitamin A, vitamin E,tocopherols and similar vitamins or provitamins occurring in the humanbody. Preservatives may be used to protect the formulation fromcontamination with pathogens. Suitable preservatives are those which areknown in the art, particularly cetyl pyridinium chloride, benzalkoniumchloride or benzoic acid or benzoates such as sodium benzoate in theconcentration known from the prior art. For the treatment formsdescribed above, ready-to-use packs of a medicament for the treatment ofrespiratory complaints are provided, containing an enclosed descriptionincluding for example the words respiratory disease, COPD or asthma, apteridine and one or more combination partners selected from thosedescribed above.

Experimental Procedures and Synthetic Examples

List of Abbreviations

-   -   ACN acetonitrile    -   APCI atmospheric pressure chemical ionization (in MS)    -   Ctrl control    -   DAD diode array detector    -   DMA N,N-dimethylacetamide′    -   DMF N,N-dimethylformamide    -   DMSO dimethyl sulfoxide    -   EI electron impact (in MS)    -   ESI electrospray ionization (in MS)    -   ex example    -   GC/MS gas chromatography with mass spectrometric detection    -   h hour(s)    -   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluoro-phosphate    -   HPLC high performance liquid chromatography    -   HPLC/MS coupled high performance liquid chromatography-mass        spectrometry    -   min minutes    -   MS mass spectrometry    -   NMR nuclear magnetic resonance    -   NMP N-Methyl-2-pyrrolidinone    -   R_(t) retention time (in HPLC)    -   sec secondary    -   TBTU        O-(1H-benzo-1,2,3-triazol-1-yl)-N,N,N′,N′-tetramethyluronium        tetrafluoroborate    -   tert tertiary    -   TFA trifluoroacetic acid    -   THF tetrahydrofurane    -   TLC thin-layer chromatography    -   UV ultraviolet absorption

Analytical Methods

HPLC Methods

Methods:

-   -   1E        -   Column: Symmetry C8, 5 μm, 3×150 mm        -   Mobile phase: A=(10 nM aqueous solution of NH₄COOH)+10% ACN;            B=ACN+10% (10 nM aqueous solution of NH₄COOH).        -   Flow rate: 1200 μL/min        -   Gradient: A (100%) for 1.5 min then to B (100%) in 10 min            for 3 min    -   1E (Hydro)        -   Column: Synergy Hydro RP80A, 4 μm, 4.6×100 mm        -   Mobile phase: A=(10 nM aqueous solution of NH₄COOH)+10% ACN;            B=ACN+10% (10 nM aqueous solution of NH₄COOH).        -   Flow rate: 1200 μL/min        -   Gradient: A (100%) for 1.5 min then to B (100%) in 10 min            for 3 min    -   Equipment:        -   Instrument: HPLC/MS ThermoFinnigan HPLC Surveyor DAD,        -   Detection: UV @ 254 nm        -   Detection: Finnigan MSQ, quadrupole        -   Ion source: APCI

Methods:

-   -   2F        -   Column: Symmetry Shield RP8, 5 μm, 4.6×150 mm        -   Mobile phase: A=(H₂O+HCOOH 0.1%)+10% ACN B=ACN+10% (H₂O+0.1%            HCOOH)        -   Flow rate: 1000 μL/min        -   Gradient: A/B (95/5%) for 1.5 min then to A/B (5/95%) in 10            min for 1.5 min    -   2M        -   Column: Symmetry Shield RP8, 5 μm, 4.6×150 mm        -   Mobile phase: A=(H₂O+HCOOH 0.1%)+10% ACN B=ACN+10% (H₂O+0.1%            HCOOH)    -   Flow rate: 1200 μL/min    -   Gradient: A/B (90/10%) for 1.5 min then to A/B (5/95%) in 10 min        for 2 min    -   Equipment:        -   Instrument: HPLC/MS ThermoFinnigan HPLC Surveyor DAD, LCQDuo            Ion Trap        -   Detection: UV λ 254 nm        -   Detection: Finnigan LCQDuo Ion Trap        -   Ion source: ESI

Method:

-   -   2FF        -   Column: Symmetry Shield RPB, 5 μm, 4.6×150 mm        -   Mobile phase: A=(H₂O+HCOOH 0.1%)+10% ACN B=ACN+10% (H₂O+0.1%            HCOOH)        -   Flow rate: 1000 μL/min        -   Gradient: A/B (95/5%) for 1.5 min then to A/B (5/95%) in 10            min for 1.5 min    -   Equipment:        -   Instrument: HPLC/MS ThermoFinnigan HPLC Surveyor DAD,            LCQFLEET Ion Trap        -   Detection: UV λ 254 nm        -   Detection: Finnigan LCQDuo Ion Trap        -   Ion source: ESI

Methods:

-   -   2Ia (isocratic)        -   Column: DAICEL Chiralpack AS-H 5 μm, 4.6×250 mm        -   Mobile phase: A=Hexane; B=EtOH A/B=98/2%        -   Flow rate: 1 ml/min    -   2Ib (isocratic)        -   Column: DAICEL Chiralpack AS-H 5 μm, 4.6×250 mm        -   Mobile phase: A=Hexane; B=EtOH A/B=95/5%        -   Flow rate: 1 ml/min    -   2Ic (isocratic)        -   Column: DAICEL Chiralpack AS-H 5 μm, 4.6×250 mm        -   Mobile phase: A=Hexane; B=EtOH A/B=70/30%    -   2J (isocratic)        -   Column: DAICEL Chiralpack AD-H 5 μm, 4.6×250 mm        -   Mobile phase: A=Hexane; B=Isopropanol A/B=98/2%        -   Flow rate: 1 ml/min    -   2Ja (isocratic)        -   Column: DAICEL Chiralpack AD-H 5 μm, 4.6×250 mm        -   Mobile phase: A=Hexane; B=Isopropanol A/B=80/20%        -   Flow rate: 1 ml/min    -   2K (isocratic)        -   Column: DAICEL Chiralcel OJ-H 5 μm, 4.6×250 mm        -   Mobile phase: A=Hexane; B=EtOH A/B=85/15%        -   Flow rate: 1 ml/min    -   2Ka (isocratic)        -   Column: DAICEL Chiralcel OJ-H 5 μm, 4.6×250 mm        -   Mobile phase: A=Hexane; B=EtOH A/B=98/2%        -   Flow rate: 1 ml/min    -   Equipment        -   Instrument: LC Agilent Technologies. HPLC 1100 Serie, DAD            Version A.        -   Detection: UV 220-300 nm

Method:

-   -   2Ha        -   Column: MERCK; Chromolith Flash; RP18e; 25×4.6 mm        -   Mobile phase: A=Water+0.1% HCOOH; B=ACN+0.1% HCOOH        -   Flow rate: 1.6 μL/min        -   Gradient:

% B Minutes 10 0.00 90 2.70 90 3.00 10 3.30

-   -   Equipment:        -   Instrument: Agilent Technology; HP 1100 Series, DAD        -   Detection: UV 190-400 nm        -   Detection: Agilent Technology; HP 1100 MSD        -   Ion source: ESI+

Methods:

-   -   2Ga        -   Column: ACQUITY UPLC BEH C18, 1.7 um, 2.1×50 mm        -   Mobile phase: A=(NH4COOH 5 mM)+10% ACN B=ACN+10% water        -   Flow rate: 700 μL/min        -   Gradient: from A/B (100/0%) to A/B (0/100%) in 2.4 min, then            A/B (0/100%) for 0.3 min    -   2Gb        -   Column: ACQUITY UPLC HSS C18, 1.7 um, 2.1×50 mm        -   Mobile phase: A=Water+0.0.5% TFA; B=ACN+0.1% water        -   Flow rate: 700 μL/min        -   Gradient: from A/B (100/0%) to A/B (0/100%) in 2.4 min, then            A/B (0/100%) for 0.3 min    -   Equipment:        -   Instrument: Acquity UPLC/MS WATERS        -   Detection: Waters PDA (total scan)        -   Detection: Waters ELSD        -   Detection: Waters SQD        -   Ion source: ESI

GC-MS Methods:

Methods:

-   -   3A        -   Column: Agilent DB-5MS, 25 m×0.25 mm×0.25 μm        -   Carrier gas: Helium, 1 ml/min constant flow        -   Oven Program: 50° C. (hold 1 min), to 100° C. in 10° C./min,            to 200° C. in 20° C./min, to 300° C. in 30° C./min    -   3B        -   Column: Agilent DB-5MS, 25 m×0.25 mm×0.25 μm        -   Carrier gas: Helium, 1 ml/min costant flow        -   Oven Program: 80° C. to 110° C. in 10° C./min (hold 40 min),            to 280° C. in 30° C./min    -   Equipment        -   Instrument: GC/MS Finnigan TRACE GC, TRACE MS quadrupole        -   Detection: TRACE MS quadrupole        -   Ion source: EI

Microwave Heating:

-   -   Discover® CEM instruments, equipped with 10 and 35 mL vessels.

Synthesis of Intermediates

Intermediate 1a

Potassium hydroxide (37.9 g, 0.67 mol) was suspended in 200 ml of dryethanol, formamidine acetate (28.1 g, 0.27 mol) and commerciallyavailable diethyl oxalpropionate (50 ml, 0.27 mol) were added and thereaction mixture was stirred under reflux overnight. The reactionmixture was cooled to room temperature and the precipitate formed wasfiltered, washed with ethanol and diethyl ether, dissolved in 200 ml ofwater and the solution obtained acidified by a 37% aqueous solution ofhydrochloric acid until pH=2. The acidic aqueous solution wasconcentrated under vacuum and the residue obtained was suspended andstirred in 100 ml of methanol. The insoluble inorganic salts werefiltered off. The solution was concentrated. 15 g (97.4 mmol) of thedesired compound were obtained.

Intermediate 1b

was synthesized in analogy to Intermediate 1a, starting from acetamidinehydrochloride.

Intermediate 1c

Diethylmethyl malonate (17 ml, 107 mmol) was added to sodium methoxide(30% in methanol, 101 ml, 547 mmol) and stirred for 15 min at 0° C. Asolution of commercially available O-methylisourea hydrochloride (14.5g, 131 mmol) in 20 ml MeOH was added dropwise to the reaction mixture.The reaction mixture was stirred for 1 h at 0° C. Then, the reaction washeated for 2 h at 65° C. The solvent was removed under vacuum. Water wasadded to the residue and heated for 10 min at 50° C. The mixture wasacidified by addition of acetic acid until pH 4 and then cooled in anice bath. The formed precipitate was filtered and washed with ice waterto give the desired product (13.8 g).

Intermediate 1d

was synthesized in analogy to intermediate 1c starting from commerciallyavailable 2,2,2,-trifluoro-acetamidine.

Intermediate 2a

Intermediate 1a (7.0 g, 45.4 mmol) was suspended in 35 ml of thionylchloride (0.45 mol), 0.10 ml of DMF was added and the reaction mixturewas refluxed for 1 h. The reaction mixture was concentrated in vacuum.8.6 g (45 mmol) of the desired product were obtained and used in thenext steps without further purification.

Intermediate 2b

was synthesized in analogy to Intermediate 2a, starting fromIntermediate 1b.

Intermediate 2c

was synthesized in analogy to Intermediate 2a starting from commerciallyavailable 6-hydroxypyrimidine-4-carboxylic acid.

Intermediate 2d

Intermediate 1c (1.9 g, 12.2 mmol) was added to phosphoryl chloride (17ml) and the reaction mixture was stirred overnight at 60° C. Thereaction mixture was cooled to 0° C. and quenched with 4 N NaOH. Then,the crude mixture was extracted with dichloromethane. The combinedorganic layers were concentrated under vacuum. The residue was purifiedby reversed phase HPLC to give the desired product.

Intermediate 2e

Commercially available 1-chloro-N,N,2-trimethylpropenylamine (70.5 μl,533 μmol) was slowly added to a solution of commercially available4-chloro-6-methoxy-pyridine-2-carboxylic acid (50 mg, 267 μmol) in 3 mldichoromethane at 0° C., and the reaction mixture was stirred for 3 h atroom temperature. The solvent was removed in vacuum to give the desiredproduct (55 mg) which was used in the next step without purification.

Intermediate 2f

Thionylchloride (11.2 ml, 155 mmol) and DMF (250 μl) were added to asolution of intermediate 1d (3.0 g, 15.5 mmol) in 9 ml dichloromethaneand the reaction mixture was refluxed for 4 h. The reaction mixture wascooled to 0° C. and quenched with 4 N NaOH. Then, the crude mixture wasextracted with dichloromethane. The combined organic layers wereconcentrated under vacuum to give the desired product (2.7 g).

Intermediate 3a

Potassium carbonate (43.34 g, 0.31 mol) was suspended in 350 ml of dryethanol. A solution of Intermediate 2a (20 g, 0.10 mol) in 10 ml ofdichloromethane was added slowly at 0° C. The reaction mixture wasallowed to reach room temperature and stirred for 1 h. Potassiumcarbonate was filtered off and the solvent was removed under vacuum. Thecrude product was purified by flash chromathography (BIOTAGE SP1; silicagel cartridge: 65i; eluent: dichloromethane/ethyl acetate=95/5%). 5.3 g(26 mmol) of the desired compound were obtained.

Intermediate 3b

was synthesized in analogy to Intermediate 3a, starting fromIntermediate 2b.

Intermediate 4a

To a solution of lithium bromide (24 g, 277.06 mmol) in 500 ml of drytetrahydrofurane, stirred under nitrogen atmosphere, copper(I) bromide(19.87 g, 138.52 mmol) was added. The reaction mixture was stirred atroom temperature until a solution was obtained. Then, the reactionmixture was cooled to 0° C. and a 0.5M solution of commerciallyavailable 4-tolyl magnesium bromide in THF (277.05 ml, 138.52 mmol) wasadded. Then, commercially available 4-chlorocarbonyl-butyric acid ethylester (19 g, 115.44 mmol) was added and the reaction mixture was stirredat 0° C. for 18 h.

500 ml of a saturated aqueous ammonium chloride solution was added andthe reaction mixture was extracted twice with dichloromethane. Theorganic phase was washed with a saturated aqueous sodium bicarbonatesolution, dried over sodium sulphate and concentrated under vacuum. Thecrude product (20 g) was used in the next step without any purification.

Intermediate 5a

To a solution of intermediate 4a (20 g, 90.80 mmol) in 50 ml oftetrahydrofurane 50 ml of water and lithium hydroxide monohydrate (11.43g, 274.40 mmol) were added and the reaction mixture was stirred at 50°C. for 1 h.

The reaction mixture was extracted with ethyl acetate and the layerswere separated. The water phase was acidified with aqueous HCl (37%)until pH 1 and then extracted with dichloromethane. The organic layerwas dried ver sodium sulfate and concentrated under vacuum. The crudeproduct was triturated with diisopropyl ether. The solvent was removedby filtration yielding the desired product (13 g, 63.10 mmol).

Intermediate 6a

A suspension of Intermediate 5a (11.5 g, 55.76 mmol) in 250 ml of waterwas cooled to 10°. Then, potassium hydroxide (7.82 g, 139.4 mmol) andsodium borohydride (1.83 g, 48.51 mmol) were added and the reactionmixture was allowed to reach room temperature and stirred for 2 h. 13 mlof a 12M aqueous hydrochloric acid was added and the reaction mixturewas extracted with ethyl acetate. The organic layer was dried oversodium sulfate and concentrated under vacuum to give the crude product(11 g, 52.82 mmol).

The following intermediates were synthesized in analogy to Intermediates4a, 5a and 6a.

synthesis in analogy to synthesis in analogy to synthesis in analogyintermediate 4a intermediate 5a to intermediate 6a Keto- Keto- Hydroxy-ester acid acid Starting Source/ Inter- Inter- Inter- Grignard Referencemediate STRUCTURE mediate STRUCTURE mediate STRUCTURE 4- ((Trifluoro-methyl)- phenyl)- magnesium bromide WO2009/73203 4b

5b

6b

Phenyl magnesium bromide Commercially available 4c

5c

6c

4-Chloro- phenyl magnesium bromide Commercially available 4d

5d

6d

3-Tolyl- magnesium bromide Commercially available 4e

5e

6e

3-((Trifluoro- methyl)- phenyl)- magnesium bromide WO2009/73203 4f

5f

6f

(6-(Trifluoro- methyl) pyridin-3-yl) magnesium bromide *) 4g

5g

6g

4-((Trifluoro- methoxy)- phenyl)- magnesium bromide Commerciallyavailable 4h

5h

6h

4-Fluoro- phenyl- magnesium bromide Commercially available 4i

5i

6i

*) 6-(Trifluoro-methyl)pyridin-3-yl)magnesium bromide was prepared byadding 5 ml of dry tetrahydrofurane and 0.061 ml (0.061 mmol) of a 1Msolution of diisobutyl aluminium hydride in hexane to magnesium turnings(3.9 g, 160 mmol) and of lithium chloride (6.27 g, 148 mmol. Thereaction mixture was stirred at 0° C. for 5 min, then a solution of of(6-(trifluoro-methyl)pyridin-3-yl)-bromide (7.5 g, 32.2 mmol) in 30 mlof dry tetrahydrofurane was added dropwise. The reaction mixture wasallowed to reach room temperature, stirred for 30 min and used directly.

Intermediate 7a

Intermediate 6a (6 g, 28.81 mmol) was dissolved in 100 ml ofdichloromethane. 1.5 ml of trifluoroacetic acid was added and thereaction mixture was stirred at room temperature for 18 h. The reactionmixture was diluted with 50 ml of dichloromethane and washed with 50 mlof a saturated aqueous sodium bicarbonate solution and water. Theorganic layer was dried over sodium sulfate and removed under vacuum togive the desired product (4.38 g (23.0 mmol).

Intermediate 8a

A solution of intermediate 7a (4.38 mg, 3.94 mmol) in 110 ml ofdichloromethane was cooled to −78° C. Then, a 1M solution ofdiisobutylaluminiumhydride (46.15 ml, 46.15 mmol) in dichloromethane wasadded dropwise. The reaction mixture was stirred at −78° C. for 120 minThe conversion into the lactol intermediate was confirmed by GC-MSanalysis of a sample of the reaction mixture treated with water andextracted with dichloromethane. 100 ml of methanol was added at −78° C.and the reaction mixture was allowed to reach room temperature. Thereaction mixture was concentrated under vacuum and the crude productobtained was triturated with ethyl ether. The precipitate was filteredoff and washed with ethyl ether. The organic layer was removed undervacuum to give the crude lactol (4.4 g, 22.9 mmol). The lactol wasdissolved in 80 ml of dry dichloromethane and cooled to 0° C. Thentriethylamine (4.96 ml, 34.33 mmol), acetic anhydride (2.54 ml, 27.46mmol) and 4-dimethylaminopyridine (279.59 mg, 2.29 mmol) were added. Thereaction mixture was allowed to reach room temperature and stirred for 1h. A saturated aqueous sodium bicarbonate solution was added and themixture was extracted with dichloromethane. The organic phase was driedover sodium sulfate and concentrated under vacuum. The residue waspurified by flash chromatography (Biotage SP1 cartridge 50 g, eluent:cyclohexane/ethyl acetate=95/5) to give desired product (4 g, 17.1mmol).

The following intermediates were synthesized in analogy to Intermediates7a and 8a.

synthesis in analogy to intermediate 7a synthesis in analogy tointermediate 8a Starting Lactol- Hydroxy-acid Lactone acetateIntermediate Intermediate STRUCTURE Intermediate STRUCTURE 6b 7b

8b

6c 7c

8c

6d 7d

8d

6e 7e

8e

6f 7f

8f

6g 7g

8g

6h 7h

8h

6i 7i

8i

Intermediate 9a

Trimethylsilylcyanide (0.52 ml, 4.16 mmol) and borontrifluoride etherate(0.27 ml, 2.22 mmol) were added to a solution of Intermediate 8a (650mg, 2.77 mmol) in 50 ml of acetonitrile under nitrogen atmosphere atroom temperature. The reaction mixture was stirred for 18 h. Thereaction mixture was concentrated under vacuum to give the desiredproduct (mixture of diastereoisomers).

GC/MS (method 3A) R_(t)=10.47 min and 10.68 min (diastereoisomericmixture, ratio trans/cis=8/2)

Intermediate 10a

Intermediate 9a was purified by flash chromatography (Biotage SP1cartridge 25 g, eluent: cyclohexane/ethyl acetate=99/1). 400 mg ofdiastereomerically pure trans stereoisomer was obtained (racemate,relative configuration assigned by NMR).

GC/MS (method 3A) R_(t)=10.47 min

Intermediate 11a

Further elution of the column gave 100 mg of the diastereomerically purecis stereoisomer (racemate, relative configuration assigned by NMR).

GC/MS (method 3A) R_(t)=10.68 min

Intermediate 11a was also obtained by epimerization of Intermediate 10a:Intermediate 10a (3.2 g, 15 mmol) was dissolved in 40 ml oftetrahydrofurane. Potassium tert-butoxide (178 mg, 1 mmol) was added andthe reaction mixture was stirred at room temperature for 0.5 h. Thesolid was removed by filtration and the reaction mixture wasconcentrated under vacuum. The crude product was purified by flashchromatography (Biotage SP1 cartridge 50 g, eluent: cyclohexane/ethylacetate=99/1). 1.45 g of the desired cis diastereoisomer was obtained.

The following intermediates were synthesized in analogy to Intermediates9a, 10a and 11a.

synthesis in analogy to synthesis in analogy to synthesis in analogy tointermediate 9a intermediate 10a intermediate 11a Starting Lactol-acetate Inter- Inter- Inter- Inter- me- me- mediate mediate STRUCTUREdiate STRUCTURE diate STRUCTURE 8b 9b

10b

11b

8c 9c

10c

11c

8d 9d

10d

11d

8e 9e

10e

11e

8f 9f

10f

11f

8g 9g

10g

11g

8h 9h

10h

11h

8i 9i

Intermediate 12a

Racemic Intermediate 11a (1.17 g, 2.06 mmol) was separated by chiralHPLC (semi-preparative column). 400 mg (1.99 mmol) were obtained assingle stereoisomer.

Chiral HPLC (method 2Ia isocratic): R_(t)=8.74 min

Intermediate 13a

Further elution of the column gave 390 mg (1.94) of the correspondingsingle enantiomer.

Chiral HPLC (method 2Ia isocratic): R_(t)=9.06 min

Absolute stereochemistry was determined by X-ray crystallography:

Absolute stereochemistry was derived from the refinement of anomalousdispersion data.

While an unambiguous assignment is not possible due to the lack of heavyatoms, the Flack parameter gave a clear tendency toward the indicatedchiral configuration.

Crystal Data: C₁₃H₁₅N₁O₁M_(r)=201.26, orthorhombic, P2₁2₁2₁,a=8.0519(16)Å, b=11.185(2)Å, c=12.637(3)Å, V=1138.2(4)Å³, Z=4,D_(X)=1.175 g/cm³, 1=1.542 Å, m=0.58 mm⁻¹, F(000)=423, T=100(1) K. DataCollection: 12235 measured reflections, 1888/1130 unique, Rint=0.079.Refinement: 138 parameters; hydrogen atoms were included as ridingatoms, S=1.02, R1=0.052 for 1393 reflections with Fo>4sig(Fo), wR=0.128(Weight w=1/[s²(Fo²)+(0.0864P)²+0.0P] where P=(Fo²+2Fc²)/3, largestdifference peak: 0.31 e/Å³; largest difference hole −0.22 e/Å³,Flack=0.2(5).

The following intermediates were separated in analogy to Intermediates12a and 13a.

Starting Chiral First Single Second syn- HPLC syn- R_(t) Single syn-R_(t) Stereo- racemate Method stereoisomer (min) STRUCTURE stereoisomer(min) STRUCTURE chemistry 11b 2Ia 12b 13.25

13b 14.33

Absolute stereo- chemistry as shown* 11c 2J 12c 9.94

13c 10.84

relative stereo- chemistry cis 11d 2K 12d 9.09

13d 9.76

relative stereo- chemistry cis 11e 2Ib 12e 7.23

13e 8.24

relative stereo- chemistry cis 11f 2K 12f 6.03

13f 6.67

relative stereo- chemistry cis 11h 2Ka 12h 13.65

13h 14.53

relative stereo- chemistry cis *Absolute stereochemistry forintermediate 12b was derived from the refinement of anomalous dispersiondata for Intemediate 12b. While an unambiguous assignment is notpossible due to the lack of heavy atoms, the Flack parameter gave aclear tendency toward the indicated chiral configuration.

Crystal Data: C₁₃H₁₂N₁O₁F₃, M_(r)=255.24, orthorhombic, P2₁2₁2₁,a=7.5726(15)Å, b=11.053(2)Å, c=14.173(3)Å, V=1186.3(4)Å³, Z=4,D_(X)=1.429 g/cm³, 1=1.542 Å, m=1.061 mm⁻¹, F(000)=528, T=100(1) K. DataCollection: 8980 measured reflections, 1900/1131 unique, Rint=0.045.Refinement: 164 parameters; hydrogen atoms were included as ridingatoms, S=1.10, R1=0.065 for 1710 reflections with Fo>4sig(Fo), wR=0.167(Weight w=1/[s²(Fo²)+(0.1147P)²+1.0917P] where P=(Fo²+2Fc²)/3, largestdifference peak: 0.43 e/Å³; largest difference hole −0.39 e/Å³,Flack=0.2(3).

Intermediate 14a

Intermediate 9a was dissolved in 20 ml of tetrahydrofurane, a 1Msolution of borane-tetrahydrofurane complex (3.28 ml, 3.28 mmol) wasadded and the reaction mixture was stirred at room temperature for 18 h.20 ml of a saturated aqueous sodium bicarbonate solution and 50 ml ofdicholometane were added. The organic layer was dried over magnesiumsulfate and concentrated under vacuum. 90 mg (0.44 mmol) of the desiredproduct were obtained.

Intermediate 15a

was synthesized in analogy to Intermediates 14a starting fromintermediate 11a

Intermediate 16a

was synthesized in analogy to Intermediates 14a starting fromintermediate 12a. Absolute stereochemistry known.

Intermediate 17a

was synthesized in analogy to intermediate 14a starting fromintermediate 13a. Absolute stereochemistry known.

The following intermediates were synthesized in analogy to Intermediates14a and 15a.

synthesis in analogy to intermediate 14a synthesis in analogy tointermediate 15a Starting Inter- Starting Inter- Intermediate mediateSTRUCTURE intermediate mediate STRUCTURE 9b 14b

11b 15b

9c 14c

11c 15c

9d 14d

11d 15d

9e 14e

11e 15e

9f 14f

11f 15f

9g 14g

11g 15g

9h 14h

11h 15h

9i 14i

The following intermediates were synthesized in analogy to Intermediates16a and 17a.

synthesis in analogy to intermediate 16a synthesis in analogy tointermediate 17a Starting Inter- Starting Inter- Stereo- Intermediatemediate STRUCTURE intermediate mediate STRUCTURE chemistry 12b 16b

13b 17b

absolute strereo- chemistry as shown 12c 16c

13c 17c

relative stereo- chemistry cis * 12d 16d

13d 17d

relative stereo- chemistry cis 12e 16e

13e 17e

relative stereo- chemistry cis 12f 16f

13f 17f

relative stereo- chemistry cis 12h 16h

13h 17h

relative stereo- chemistry cis * Shown stereochemistry corresponds tostereoselective synthesis of intermediate 39d using (S,S)-teth-TsDpenruthenium chloride (Johnson Matthey Catalysts).

Intermediate 18a

3-Methoxy-tetrahydro-pyran-4-one* (1 g, 7.68 mmol), commerciallyavailable (R)-(+)-1-phenylethylamine (0.99 ml, 7.68 mmol) andRaney-Nickel (200 mg) in 10 ml of dry ethanol were stirred under ahydrogen atmosphere (5 bar) for 15 days. The reaction mixture wasdiluted with 20 ml of methanol and 20 ml of tetrahydrofurane, stirredfor 15 minutes, filtered on a celite pad and concentrated under vacuum.The crude product was loaded on a SCX cartridge (50 g). The cartridgewas washed with methanol and the desired product was eluted with a 7 Msolution of ammonia in methanol. The basic organic phase wasconcentrated under vacuum and the crude product was purified by flashchromatography (dichloromethane/methanol=98/2%) to obtain 710 mg (3.02mmol) of the desired product as single stereoisomer (diastereoisomericpurity confirmed and relative cis stereochemistry assigned by NMR).

GC/MS (method 3B) R_(t)=35.04 min

* Tetrahedron Letters, 2005, 447-450

Intermediate 18b

was synthesised in analogy to Intermediate 18a, starting from3-Methoxy-tetrahydro-pyran-4-one and commercially available(S)-(−)-1-phenylethylamine (diastereoisomeric purity confirmed andrelative cis configuration assigned by NMR).

GC/MS (method 3B) R_(t)=35.04 min

Intermediate 19a

Intermediate 18a (1.18 g, 5.01 mmol), Pd/C 10% (200 mg) and acetic acid(0.3 ml, 5.01 mmol) in 20 ml of methanol were stirred under a hydrogenatmosphere (5 bar) for 18 h. The reaction mixture was diluted with 20 mlof methanol, stirred for 15 minutes, filtered on a celite pad andconcentrated under vacuum. The crude product was loaded on a SCXcartridge (50 g). The cartridge was wash with methanol and the desiredproduct was eluted with a 7 M solution of ammonia in methanol. The basicorganic phase was concentrated under vacuum and 513 mg (3.91 mmol) ofthe desired product were obtained as single stereoisomer

Intermediate 19b

was synthesised in analogy to Intermediate 19a, starting fromIntermediate 18b.

Intermediate 20a

N-methyl-N-piperidin-4-yl-methanesulfonamide hydrochloride (11 g, 47.91mmol; WO2009/47161) was suspended in 200 ml of 1,2-dichloroethane,N,N-diisopropylethylamine (17.12 ml, 96.17 mmol) and commerciallyavailable 1-(tert-butoxycarbonyl)-piperidin-4-one (9.58 g, 48.08 mmol)were added and the reaction mixture was stirred at room temperature for30 min. Sodium triacetoxyborohydride (12.23 g, 57.50 mmol) was added andthe reaction mixture was stirred at room temperature for 72 h. Thereaction mixture was diluted with dichloromethane and washed with anaqueous saturated sodium bicarbonate solution. The organic phase wasdried over sodium sulfate and concentrated under vacuum. The crudeproduct was purified by flash chromatography (Biotage SP1; silica gelcartridge: 65i; eluent: ethyl acetate/methanol=50/50%) to obtain 7.2 g(19.2 mmol) of the desired compound.

Intermediate 21a

Intermediate 20a (7.2 g, 19.2 mmol) was suspended in 20 ml of1,4-dioxane, a 4M solution of hydrochloric acid (48 ml, 192 mmol) in1,4-dioxane was added dropwise. The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was concentrated undervacuum. 6.3 g (18 mmol) of the desired compound were obtained.

The following intermediates were synthesized in analogy to Intermediates20a and 21a.

synthesis in analogy synthesis in analogy to intermediate 20a tointermediate 21a Carba- Di- mate amino Starting Source/ Starting Source/Inter- Inter- intermediate Reference intermediate Reference mediateSTRUCTURE mediate STRUCTURE 1-(tert- butoxycar- bonyl)-4- oxopiperidinecommercially available 19a — 20b

21b

1-(tert- butoxycar- bonyl)-4- oxopiperidine commercially available 19b —20c

21c

1-(tert- butoxycar- bonyl)-4- oxopiperidine Commercially availableN-methyl-N- piperidin-4-yl- ethanesulfon- amide Prepared in analogy toN-methyl-N- piperidin-4- yl-methane- sulfonamide starting fromethansulfonyl chloride (see intermediate 20a) 20d

21d

3-Methoxy- tetrahydro-pyran- 4-one Tetrahedron Letters, 2005, 447-4504-amino- piperidine- 1-carboxylic acid tert-butyl- ester Commerciallyavailable 20e

21e

3-Fluoro- tetrahydro-pyran- 4-one WO2003/93231 4-amino- piperidine-1-carboxylic acid tert-butyl- ester Commercially available 20f

21f

3H-spiro[1- benzofuran- 2,4′-piperidine] Commercially available 1-(tert-butoxycarbonyl)- piperidin-4-one Commercially available 20g

21g

Intermediate 22

Commercially available piperidin-4-yl-carbamic acid tert-butyl ester (6g, 30 mmol) and commercially available1-(benzyloxycarbonyl)-4-oxopiperidine (9.6 g, 48 mmol) were dissolved in50 ml of dichloromethane and the reaction mixture was stirred at roomtemperature for 30 min; sodium triacetoxyborohydride (12.23 g, 57.5mmol) was added and the reaction mixture was stirred at room temperatureovernight. The reaction mixture was diluted with dichloromethane andwashed with an aqueous saturated sodium bicarbonate solution. Theorganic phase was dried over sodium sulfate and concentrated undervacuum. The crude product was treated with acetone/isopropyl ether andthe precipitate obtained was filtered off. 8.4 g (20 mmol) of thedesired product were obtained.

Intermediate 23

A solution of intermediate 22 (8.4 g, 20 mmol) in 150 ml of 1,4-dioxanewas cooled to 0° C. Then, 12.6 ml (50 mmol) of a 4M solution ofhydrochloric acid in 1,4-dioxane were added dropwise; the reactionmixture was allowed to warm to room temperature and stirred overnight.The precipitate was filtered off and dried at 50° C. under vacuum togive the desired product (6 g, 15 mmol).

Intermediate 24

Intermediate 23 (6.0 g, 15 mmol) was suspended in 55 ml ofdichloromethane; triethylamine (6.43 ml, 46 mmol) was added and thereaction mixture was cooled to 0° C. and stirred for 30 minMethanesulfonyl chloride (1.43 ml, 18 mmol) in 5 ml of dichloromethanewas added dropwise. The reaction mixture was stirred at 0° C. for 1 h;then water was added and the reaction mixture was extracted withdichloromethane. The organic phase was washed with an aqueous saturatedsodium bicarbonate solution, with brine, dried over sodium sulfate andconcentrated under vacuum. The crude product was treated withdiisopropyl ether, the precipitate was filtered off and dried. 5 g (13mmol) of the desired product were obtained.

Intermediate 25

Intermediate 24 (5 g, 13 mmol) was dissolved in 50 ml of methanol;acetic acid (1.5 ml, 25.3 mmol) and Pd/C 10% (500 mg) were added insequence and the reaction mixture was stirred under a hydrogenatmosphere (3 bar) at room temperature for 5 days. The reaction mixturewas filtered on a celite pad and the organic phase was loaded on a SCXcartridge (10 g). After washing with methanol, the desired compound waseluted with a 2M solution of ammonia in methanol. 3.7 g (4.6 mmol) ofthe desired product were obtained.

Intermediate 26a

Intermediate 25 (1.1 g, 4.21 mmol) was suspended in 20 ml of drydichloromethane, N,N-diisopropylethylamine (1.47 ml, 8.42 mmol) and DMF(137 nl, 1.67 mmol) were added and the reaction mixture was stirredunder nitrogen atmosphere and cooled to 0° C. Intermediate 2a (812 mg,4.21 mmol) in 5 ml of dichloromethane was added dropwise and thereaction mixture was allowed to warm to room temperature and stirred for1.5 h; the reaction mixture was diluted with dichloromethane and washedwith an aqueous saturated sodium bicarbonate solution. The organic phasewas separated, dried over sodium sulfate and concentrated under vacuum.The crude product was purified by flash chromatography (isolute silicagel cartridge: 10 g; eluent: dichloromethane/methanol=95/5%). 1.0 g(2.41 mmol) of the title compound were obtained.

The following intermediates were synthesized in analogy to Intermediate26a.

Chloro- Core Piperidine pyrimidine Intermediate IntermediateIntermediate STRUCTURE 2a 21a 26b

2a 4-Methoxy- [1,4′]bi piperidinyl (commercially available) 26c

2b 21a 26d

2a 21d 26e

2c 21a 26f

2c 21b 26g

2c 21c 26h

2a 21e 26i

Intermediate 26j

Intermediate 2e (55 mg, 267 μmol) was added to a solution oftriethylamine (111 μl, 800 μmol) and Intermediate 21c (73 mg, 291 μmol)in 2.5 ml dichloromethane, and the reaction mixture was stirred for 15min at room temperature. The reaction mixture was diluted withdichloromethane, washed with a saturated aqueous sodium bicarbonatesolution, dried over sodium sulfate and concentrated under vacuum. Theresidue was purified by reversed phase HPLC to give the desired product(133 mg).

Intermediate 27a

Intermediate 3a (976 mg, 4.6 mmol) and N,N-diisopropylethylamine (0.9ml, 5.24 mmol) were dissolved in 15 ml of dry 1,4-dioxane; intermediate17a (430 mg, 2.09 mmol) was added and the reaction mixture was refluxedfor 6 h. The reaction mixture was cooled to room temperature, water wasadded and the reaction mixture was extracted with dichloromethane; theorganic phase was washed with an aqueous saturated sodium bicarbonatesolution and concentrated under vacuum. 770 mg (2.08 mmol) of thedesired compound were obtained as crude product. Absolutestereochemistry known.

Intermediate 28a

Intermediate 27a (770 mg, 2.08 mmol) was dissolved in 8 ml oftetrahydrofurane and a solution of LiOH (262 mg, 6.24 mmol) in 8 ml ofwater was added. The reaction mixture was stirred at 70° C. for 1 hourand then concentrated under vacuum. 20 ml of water was added and thereaction mixture was acidified with 5 ml of a 4M solution ofhydrochloric acid in water. The aqueous phase was extracted withdichloromethane (2×20 ml). The organic phase was dried over sodiumsulfate and removed under vacuum. 670 mg (1.96 mmol) of the desiredproduct were obtained. Absolute stereochemistry known.

The following intermediates were synthesized in analogy to Intermediates27a and 28a.

Synthesis in analogy to intermediate 27a Synthesis in analogy tointermediate 28a Core Ester Acid Inter- Inter- Inter- Stereo- mediateAmine mediate STRUCTURE mediate STRUCTURE chemistry 3a 16a 27b

28b

absolute stereo- chemistry as shown 3a 16b 27c

28c

absolute stereo- chemistry as shown 3a 17b 27d

28d

absolute stereo- chemistry as shown 3a 16c 27e

28e

relative stereo- chemistry cis 3a 17c 27f

28f

relative stereo- chemistry cis 3a 16d 27g

28g

relative stereo- chemistry cis 3a 17d 27h

28h

relative stereo- chemistry cis 3a 16e 27i

28i

relative stereo- chemistry cis 3a 17e 27j

28j

relative stereo- chemistry cis 3b 16e 27k

28k

relative stereo- chemistry cis 3b 17e 27l

28l

relative stereo- chemistry cis 3a 16f 27m

28m

relative stereo- chemistry cis 3a 17f 27n

28n

relative stereo- chemistry cis 3a 16h 27o

28o

relative stereo- chemistry cis 3a 17h 27p

28p

relative stereo- chemistry cis 3a 42 27pa

28pa

relative stereo- chemistry cis 3a 15a 27pb

28pb

relative stereo- chemistry cis

Intermediate 27q

Commercially available 2-chloro-3-methylpyridine-4-carboxylic acid ethylester (243 mg, 1.22 mmol), Intermediate 17a (250 mg, 1.22 mmol),palladium (II) acetate (27 mg, 0.12 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (379 mg, 0.61 mmol) andsodium tert-butoxide (163 mg, 1.07 mmol) were suspended in 20 ml of1,2-dimethoxyethane and refluxed for 12 h. The reaction mixture wasdiluted with dichloromethane, washed with a saturated aqueous sodiumbicarbonate solution, dried over sodium sulfate and concentrated undervacuum. The crude product was purified by flash chromatography (isolutesilica gel cartridge: 10 g; eluent: cyclohexane/ethyl acetate=90/10%).70 mg (0.19 mmol) of the desired product were obtained. Absolutestereochemistry known.

Intermediate 28q

was synthesized in analogy to Intermediates 28a starting fromintermediate 27q

The following intermediates were synthesized in analogy to Intermediates27q and 28q.

Synthesis in analogy to intermediate 27q Synthesis in analogy tointermediate 28q Core Ester Acid Inter- Inter- Inter- Stereo- mediateAmine mediate STRUCTURE mediate STRUCTURE chemistry 3a 16c 27r

28r

relative stereo- chemistry cis

Intermediate 29a

Commercially available 3-fluoro-4-methylbenzaldehyde (2.6 g, 18.82 mmol)was dissolved in 30 ml of tetrahydrofurane and the reaction mixture wascooled to −78° C. under nitrogen atmosphere. 60 ml of a cooled 0.5 Msolution of (pent-4-enyl)magnesium bromide (Liebigs Annalen der Chemie1982, 1478) was added and the reaction was stirred at −78° C. for 1 h.The reaction mixture was quenched with an saturated aqueous ammoniumchloride solution and extracted with dichloromethane. The organic phasewas separated, dried on sodium sulfate and concentrated under vacuum.3.9 g of a crude oil were obtained.

The following intermediates were synthesized in analogy to intermediate29a.

Source/ Inter- Aldehyde Reference mediate STRUCTURE 2-(4-formyl-phenyl)-2- proprionitrile Commer- cially available 29b

5- trifluoromethyl- furan-2- carbaldehyde Commer- cially available 29c

Intermediate 30a

Sodium bicarbonate (4.72 g, 56.18 mmol) was suspended in 100 ml ofacetonitrile and, under nitrogen atmosphere, intermediate 29a (3.9 g,18.73 mmol) and iodine (14.26 g, 56.18 mmol) were added. The reactionmixture was stirred at room temperature for 30 minutes, then a 10% watersolution of sodium thiosulfate was added. The reaction mixture wasextracted with diethyl ether and the organic phase was separated, driedon sodium sulfate and concentrated under vacuum. The crude product waspurified by flash chromatography (SP1 SNAP cartridge 50 g; eluent:cyclohexane/dichloromethane=95/5%). 2.5 g (7.48 mmol) of the desiredproduct were obtained.

The following intermediates were synthesized in analogy to intermediate30a.

Starting intermediate Intermediate STRUCTURE 29b 30b

29c 30c

Intermediate 31a

Intermediate 30a (2.5 g, 7.48 mmol) was dissolved in 40 ml of DMF and,under nitrogen atmosphere, potassium phtalimide (1.66 g, 8.98 mmol) wasadded. The reaction mixture was warmed to 90° C. for 4 h, then cooled toroom temperature and diluted with 100 ml of a saturated aqueous sodiumbicarbonate solution. The reaction mixture was extracted with diethylether and the organic phase was separated, dried on sodium sulfate andconcentrated under vacuum. 2.2 g of the crude product were obtained,

Intermediate 32a

The crude product (2.2 g) was precipitated with 100 ml of acyclohexane/ethyl acetate=50/50% solution and 1.8 g (5.06 mmol) of thedesired cis racemate were obtained (stereochemistry assigned by 1H-NMR).

The following intermediates were synthesized in analogy to intermediate31a and 32a.

Synthesis in analogy to intermediate 31a Synthesis in analogy tointermediate 32a Starting inter- Inter- Inter- mediate mediate STRUCTUREmediate STRUCTURE 30b 31b

32b

30c 31c

Intermediate 33a

Intermediate 32a (200 mg, 0.57 mmol) was suspended in 5 ml of methanoland hydrazine hydrate (0.21 ml, 4.41 mmol) was added. The reactionmixture was stirred at room temperature for 2 h, then it wasconcentrated under vacuum. The residue was treated with dichloromethane,the solid residue was filtered off and the filtrate was concentratedunder vacuum to yield 120 mg of the crude amine.

The following intermediates were synthesized in analogy to intermediate33a.

Starting intermediate Intermediate STRUCTURE 32b 33b

31c 33c

Intermediate 34

N,N-diisopropylethylamine (213 μl, 1.15 mmol) was added to a mixture ofintermediate 15a (94 mg, 461 μmol) and commercially available4,6-dichloro-2-trifluoromethyl-pyrimidine (100 mg, 461 μmol) in 2 mlNMP. The reaction mixture was heated in the microwave for 1 h at 120° C.The mixture was purified by reversed phase HPLC to give the desiredproduct (95 mg).

Intermediate 35

A mixture of intermediate 34 (95 mg, 246 μmol), palladium acetate (5.5mg, 25 μmol), 1,1′-bis(diphenylphosphino)-ferrocene (13 mg, 25 μmol),sodium acetate (60 mg, 739 μmol) in 5 ml methanol and 5 ml DMF wasstirred under a carbon monoxide atmosphere (5 bar) over night at 70° C.The mixture was filtered and concentrated in vacuum. The residue waspurified by reversed phase HPLC to give the corresponding ester (88 mg,168 μmol).

Lithium hydroxide (28 mg, 672 μmol) was added to a solution of the ester(88 mg, 168 μmol) in 3 ml THF and 3 ml water. The reaction mixture washeated for 15 min at 100° C. Then, the solvent was removed in vacuum andthe residue was purified by reversed phase HPLC to give the desiredproduct (61 mg).

The following intermediates were synthesised in analogy to Intermediate34 and 35.

Synthesis in analogy to intermediate 34 Synthesis in analogy tointermediate 35 Core Chloro Acid Inter- Source/ Inter- Inter- Stereo-mediate Reference Amine mediate STRUCTURE mediate STRUCTURE chemistry4,6-dichloro-2- trifluoromethyl- pyrimidine Commer- cially available 16h34a

35a

relative stereo- chemistry cis 4,6-dichloro-2- trifluoromethyl-pyrimidine Commer- cially available 16b 34b

35b

absolute stereo- chemistry as shown 4,6-dichloro- 2-methoxy- pyrimidineCommer- cially available 17a 34c

35c

absolute stereo- chemistry as shown 4,6-dichloro- 2-methoxy- pyrimidineCommer- cially available 16b 34d

35d

absolute stereo- chemistry as shown 4,6-dichloro- 2-methoxy- pyrimidineCommer- cially available 16h 34e

35e

relative stereo- chemistry cis 2d — 17a 34f

35f

absolute stereo- chemistry as shown 2d — 16b 34g

35g

absolute stereo- chemistry as shown 2d — 16h 34h

35h

relative stereo- chemistry cis 2d — 16c 34i

35i

relative stereo- chemistry cis 2f — 16c 34j

35j

relative stereo- chemistry cis

Intermediate 36

Commercially available 4-chloro-3-methyl-picolinate (100 mg, 0.5 mmol),Intermediate 17a (205 mg, 1 mmol) and N,N-diisopropyl-ethyl-amine (0.18ml, 1 mmol) were dissolved in 3 ml of N,N-dimethylacetamide and refluxedovernight. The reaction mixture was purified by preparative LC/MS(reverse phase). 120 mg (0.35 mmol) of the desired product wereobtained. Absolute stereochemistry known.

The following synthesis sequence allows the preparation of Intermediates16b, 16c, 16h, 17a, and preparation of Intermediate 42:

Intermediate 37a

To a solution of commercially available 4-(trifluoromethyl)-benzoylchloride (25 g, 112 mmol) in 250 ml dry tetrahydrofurane under nitrogenatmosphere, dimethylamine dihydrochloride (14.7 g, 180 mmol) andpotassium carbonate (49.62 g, 360 mmol) were added at 0° C. The reactionmixture was stirred at room temperature for 18 h. The solvent wasremoved under vacuum, the crude product was dissolved in ethyl acetate.The organic phase was washed with brine, dried over sodium sulfate andconcentrated under vacuum. The crude product was used in the next stepwithout any purification.

Intermediate 38a

Intermediate 37a (25 g) was dissolved in 125 ml of dry tetrahydrofuraneand the reaction mixture was cooled to 0° C. 350 ml of a cooled 0.5 Msolution of (pent-4-enyl)magnesium bromide (Liebigs Annalen der Chemie1982, 1478) was added and the reaction mixture was stirred at roomtemperature for 18 h. The reaction mixture was quenched with a saturatedaqueous ammonium chloride solution. The organic phase was separated,dried over sodium sulfate and concentrated under vacuum. The crudeproduct was purified by flash chromatography to give 25 g of the desiredproduct.

Intermediate 39a

Intermediate 38a was added dropwise to a suspension of (S,S)-teth-TsDpenruthenium chloride (20 mg, 0.032 mmol; Johnson Matthey Catalysts) in 200ml formic acid/triethylamine complex under argon atmosphere.

The reaction mixture was warmed to 70° C. for 18 h. Then, water wasadded and the reaction mixture was extracted with diethyl ether. Theorganic phase was separated, dried over sodium sulfate and concentratedunder vacuum. The crude product (40 g) was used in the next step withoutany purification.

Stereochemistry in analogy to Organic Letters 2000, 1749-51.

The following intermediates were synthesized in analogy to Intermediates37a, 38a and 39a.

synthesis in analogy synthesis in analogy synthesis in analogy tointermediate 37a to intermediate 38a to intermediate 39a Starting AmideKeton Alcohol Benzoyl Inter- Inter- Inter- Stereo- chloride Sourcemediate STRUCTURE mediate STRUCTURE mediate STRUCTURE chemistry4-methyl- benzoyl chloride Commercially available 37b

38b

39b

in analogy to Organic Letters 2000, 1749-51 4-(trifluoro- methoxyl)ben-zoyl chloride Commercially available 37c

38c

39c

in analogy to Organic Letters 2000, 1749-51 Benzoyl chlorideCommercially available 37d

38d

39d

in analogy to Organic Letters 2000, 1749-51 4-(trifluoro-methylthio)ben- zoyl chloride Chlorination of commercially available 4-(trifluorometh- ylthio) benzoic acid using thi- onylchloride 37e

38e

39e

in analogy to Organic Letters 2000, 1749-51

Intermediate 40a

To a suspension of sodium bicarbonate (40.6 g, 482 mmol) in 600 ml ofacetonitrile, a solution of Intermediate 39a (40 g) in 100 ml ofacetonitrile was added, followed by the addition of iodine (122 g, 482mmol). The reaction mixture was stirred at room temperature for 1 h,then 1000 ml of a saturated aqueous Na₂S₂O₃ solution were added. Themixture was extracted with diethyl ether. Then, the organic phase wasseparated, dried over sodium sulfate and concentrated under vacuum. Thecrude product was purified by flash chromatography to yield 29 g of thedesired cis stereoisomer.

Relative stereochemistry was assigned by 1H-NMR.

Intermediate 41a

Commercially available phthalimide potassium salt (17.4 g, 94.0 mmol)was added to a solution of Intermediate 40a (29 g, 78.4 mmol) in 250 mlDMF. The reaction mixture was stirred at 90° C. for 18 h. The reactionmixture was concentrated under vacuum, diethyl ether was added and theorganic phase was washed with an aqueous 1 M sodium hydroxide solution.The organic layer was separated, dried over sodium sulfate andconcentrated under vacuum. The crude product (28.7 g) wasre-crystallised using 350 ml of methylcyclohexane. 9.5 g ofenantiomerically enriched product were obtained.

Enantiomerical purity was determined by chiral HPLC (Method 2Ja):

R_(t) (preferred stereoisomer)=6.69 min

R_(t) (second stereoisomer)=6.00 min

Repeated re-crystallisations with methylcyclohexane allowed to increasethe yield of the enantiopure preferred stereoisomer.

The following intermediates were synthesized in analogy to Intermediates40a and 41a.

synthesis in analogy to intermediate 40a synthesis in analogy tointermediate 41a Starting Iodo Ftalimide Chiral Inter- Inter- Inter-HPLC mediate mediate STRUCTURE mediate STRUCTURE method R_(t) (min) 39b40b

41b

Method 2Ja R_(t) (preferred s stereoisomer) = 6.27 R_(t) (secondstereoisomer) = 5.62 39c 40c

41c

Method 2Ja R_(t) (preferred stereoisomer) = 6.14 R_(t) (secondstereoisomer) = 5.64 39d 40d

41d

Method 2Ja R_(t) (preferred stereoisomer) = 6.58 R_(t) (secondstereoisomer) = 5.95 39e 40e

41e

Method 2Ja R_(t) (preferred stereoisomer) = 6.73 R_(t) (secondstereoisomer) = 5.86

Intermediate 16b

Ethanolamine (8.84 ml, 146.4 mmol) was added to a solution ofIntermediate 41a (9.5 g, 24.4 mmol) in 100 ml of toluene. The reactionmixture was stirred at 70° C. for 3 h. Then, the mixture was cooled toroom temperature and diluted with water and ethyl acetate. The organicphase was separated and washed with an aqueous 1M solution of sodiumhydroxide, dried over sodium sulfate and concentrated under vacuum togive the desired product (6.1 g). The crude product was used in the nextstep without any purification.

The following intermediates were synthesized in analogy to Intermediate16b.

Starting Amine Inter- Inter- mediate mediate STRUCTURE 41b 17a

41c 16h

41d 16c

41e 42

Intermediate 43

Intermediate 28pb (870 mg, 2.55 mmol), HATU (1.07 g, 2.8 mmol) andN,N-diisopropyl-ethylamine (1.1 ml, 6.4 mmol) in 6 ml DMF were stirredat room temperature for 15 min 4-Piperidone (345 mg, 2 6 mmol) was addedand the reaction mixture was stirred at room temperature overnight. Thereaction mixture was treated with 80 ml of a 5% aqueous solution ofsodium hydroxide and extracted with ethyl acetate. The organic phase waswashed with brine, dried over sodium sulfate and concentrated undervacuum. The crude product was purified by flash chromatography to give843 mg (2.0 mmol) of the desired product.

SYNTHESIS OF EXAMPLES

The examples of this invention are synthesized according to thefollowing general synthetic procedures:

Synthetic Procedure A:

Examples: 1-28; 28a-28n

Synthetic Procedure B:

Examples: 29-53; 53a-53z; 53aa-53am

Synthetic Procedure C:

Examples: 54, 54a

Synthetic Procedure D:

Examples: 55-59

For synthetic procedure D the L₂ group represents a linker wherein L₂ isa group selected from among —C₀-C₄-alkylene, preferred wherein L₂ is agroup selected from among a bond, —CH₂—, —CH₂—CH₂—, and —(CH₂)₃—, mostpreferred wherein L₂ denotes a bond (which reflects examples 55 to 59);

wherein m is 1 or 2;

wherein Y₁ is a group selected from among —H, —C₁-C₆-alkyl,—C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl, —C₃-C₈-cycloalkyl, and—C₃-C₈-heterocyclyl, wherein said —C₃-C₈-heterocyclyl optionallycomprises nitrogen and/or —SO₂— in the ring, more preferred wherein Y₁is a group selected from —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl,—C₃-C₈-cycloalkyl, and —C₃-C₈-heterocyclyl, most preferred wherein Y₁denotes —C₆-aryl (which reflects examples 55 to 59);

and wherein the group Y₁ is optionally substituted with the group R₂₁,wherein R₂₁ is selected from among —OH, —OCH₃, —CF₃, —COO—C₁-C₄-alkyl,—OCF₃, —CN, -halogen, —C₁-C₄-alkyl, ═O, and —SO₂—C₁-C₄-alkyl, morepreferred wherein R₂₁ denotes —COO—C₁-C₄-alkyl. In the case that R₂₁denotes —COO—C₁-C₄-alkyl the compound (XII) is modified by an additionalstep which results in a transformation of R₂₁ to R_(21′), whereinR_(21′) denotes —COOH (which reflects examples 55 to 59).

Synthetic Procedure E:

Example: 60

For synthetic procedure E the CYC group represents a group selected fromamong —C₀-C₄-alkylene(R₂₀,R_(20′)), more preferred wherein CYC isselected from among —C₀-alkylene(R₂₀,R_(20′)) whereas R₂₀ and R_(20′)together form a spiro-C₃-C₈-carbocycle or spiro-C₃-C₈-heterocyclecomprising one or more groups selected from O in the ring and whereinsaid spirocycle is optionally further bi-valently substituted by anannellated ring forming group selected from among —C₁-C₆-alkylene,—C₂-C₆-alkenylene, and —C₄-C₆-alkynylene as well as wherein saidspirocycle is optionally further substituted by R₂₁, most preferredwherein the CYC group denotes —C₀-alkylene(R₂₀,R_(20′)) whereas R₂₀ andR_(20′) together form a spiro-C₅-carbocycle wherein said spirocycle isfurther bi-valently substituted by an annellated ring forming groupselected from —C₄-alkenylene and wherein said spirocycle is furthersubstituted by R₂₁ (which reflects examples 60);

wherein m is 1 or 2, more preferred wherein m is 1;

and wherein R₂₁ is selected from among —H, —OH, —OCH₃, —CF₃,—COO—C₁-C₄-alkyl, —OCF₃, —CN, -halogen, —C₁-C₄-alkyl, ═O, and—SO₂—C₁-C₄-alkyl, more preferred wherein R₂₁ denotes —COO—C₁-C₄-alkyl.In the case that R₂₁ denotes —COO—C₁-C₄-alkyl the compound (XV) ismodified by an additional step which results in a transformation of R₂₁to R_(21′), wherein R_(21′) denotes —COOH (which reflects example 60).

Example 1

Intermediate 26b (60 mg, 0.14 mmol), Intermediate 17a (28.6 mg, 0.14mmol) and N,N-diisopropyl-ethyl amine (0.05 ml, 0.31 mmol) in 0.5 ml ofdry 1,4-dioxane were mixed in a microwave vial and reacted in thefollowing conditions: Power 100, Ramp 5 min, Hold 2 h, Temperature 150°C., Pressure 150 psi, Stirring. The reaction mixture was concentratedunder vacuum and diluted with dichloromethane. The organic phase waswashed with an aqueous saturated sodium bicarbonate solution, dried oversodium sulfate and concentrated under vacuum. The crude product waspurified by reverse phase preparative HPLC. 40 mg (0.07 mmol) of thedesired product were obtained.

HPLC (Method 2M): R_(t). (min)=6.00

[M+H]⁺=599

The following examples were synthesized in analogy to the preparation ofExample 1

Inter- HPLC Ex me- [M + R_(t•) # MOLSTRUCTURE diate Amine H]⁺ (min)Method  2

26b 17b 653  9.53 1E (Hydro)  3

26c 15f 576 10.62 1E (Hydro)  4

26c 15b 576 10.96 1E (Hydro)  5

26b 16d 619  9.81 1E (Hydro)  6

26b 17d 619  9.85 1E (Hydro)  7

26b 16f 653  7.21 2F  8

26b 17f 653  7.09 2F  9

26c 17a 585  9.24 1E (Hydro) 10

26b 14c 585  8.62 and  9.08 1E (Hydro) 11

26c 15c 585  9.03 1E (Hydro) 12*

26b 15c 585  8.95 1E (Hydro) 13*

26b 15c 585  8.72 1E (Hydro) 14

26b 14i 603  8.6 1E (Hydro) 15

26b 14d 619  9.18 and  9.68 1E (Hydro) 16

26b 15d 619  9.77 1E (Hydro) 17

26b 15a 599  8.98 1E (Hydro) 18

26d 15a 613  9.90 1E (Hydro) 19

26b 16a 599  9.4 1E (Hydro) 20

26d 17a 613  9.79 1E (Hydro) 21

26b 17e 599  9.48 1E (Hydro) 22

26d 17e 613  9.98 1E (Hydro) 23

26b 16e 599  9.53 1E (Hydro) 24

26b 16b 653  9.53 1E (Hydro) 25

26b 15g 654  8.83 1E (Hydro) 26

26b 15h 669 10.38 1E (Hydro) 27

26e 15d 633  9.47 1E (Hydro) 28

26d 16e 613  9.98 1E (Hydro) 28a

26b 15b 653  9.79 1E (Hydro) 28b

26b 33c 643  8.95 and  9.28 1E (Hydro) 28c

26i 33b 556 10.08 1E (Hydro) 28d

26b 33b 617 10.05 1E (Hydro) 28e

26i 33c 582  8.70 and  9.07 1E (Hydro) 28f

26b 33b 652  9.48 1E (Hydro) 28g

26f 17a 585  1.83 2Ha 28h

26g 17a 524  1.77 2Ha 28i

26h 17a 524  1.78 2Ha 28j

26h 16b 578  1.91 2Ha 28k

26g 16b 578  1.95 2Ha 28l

26g 16h 594  1.96 2Ha 28m

26h 16h 594  1.96 2Ha *Ex 12 and 13 were obtained by chiral HPLCseparation of ex 11: Ex 12: Chiral HPLC (method 21c isocratic): R_(t) =10.94 min Ex 13: Chiral HPLC (method 21c isocratic): R_(t) = 12.93 min

Example 28n

Intermediate 17a (35 mg, 170 μmol) and intermediate 26j (127 mg, 256μmol) were added to 1.5 ml toluene and 0.5 ml dioxane. Then, caesiumcarbonate (94 mg, 290 μmol), tris(dibenzylideneacetone)dipalladium (15mg, 17 μmol) and XPhos (34 mg, 71 μmol) were added and the reactionmixture was stirred over night at 110° C. under argon atmosphere. Thereaction mixture was diluted with ethyl acetate, washed with a saturatedaqueous sodium bicarbonate solution, dried over sodium sulfate andconcentrated under vacuum. The residue was purified by reversed phaseHPLC to give the desired product (35 mg).

HPLC (Method 2HA): R_(t). (min)=1.18

[M+H]⁺=553

Example 29

Intermediate 28a (70 mg, 0.21 mmol), TBTU (65.8 mg, 0.20 mmol) andN,N-diisopropyl-ethylamine (0.11 ml, 0.62 mmol) in 5 ml DMF were stirredat room temperature for 5 min Intermediate 21c (59 mg, 0.21 mmol) wasadded and the reaction mixture was stirred at room temperatureovernight. The reaction mixture was concentrated under vacuum and thecrude product was dissolved in dichloromethane. The organic phase waswashed with an aqueous saturated sodium bicarbonate solution, dried oversodium sulfate and concentrated under vacuum. The crude product waspurified by flash chromatography (Si Isolute cartridge (5 g); eluent:dichloromethane/MeOH=96/4%). 45 mg (0.08 mmol) of the desired productwere obtained.

HPLC (Method 1E Hydro): R_(t). (min)=8.50

[M+H]⁺=538

The following examples were synthesized in analogy to the preparation ofExample 29.

Inter- HPLC me- [M + R_(t•) Ex # STRUCTURE diate Amine H]⁺ (min) Method30

26a 21b 538  9.33 1E (Hydro) 31

28b 21b 538  9.55 1E (Hydro) 32

28i 21b 538  9.75 1E 33

28i 21c 538  9.76 1E 34

28k 21b 552  9.79 1E (Hydro) 35

28k 21c 552 10.2 1E 36

28d 21b 592  9.27 1E (Hydro) 37

28d 21c 592  9.28 1E (Hydro) 38

28e 21c 524  8.64 1E (Hydro) 39

28f 21c 524  8.47 1E (Hydro) 40

28e 21b 524  8.66 1E (Hydro) 41

28g 21c 558  7.14 2F 42

28g 21b 558  7.04 2F 43

28h 21c 558  7.17 2F 44

28h 21b 558  7.17 2F 45

28m 21c 592  9.89 1E (Hydro) 46

28m 21b 592  9.73 1E (Hydro) 47

28n 21c 592  9.65 1E (Hydro) 48

28j 21b 538  9.70 1E 49

28j 21c 538  9.63 1E 50

28l 21b 552 10.1 1E 51

28l 21c 552 10.18 1E 52

28c 21c 592  9.30 1E (Hydro) 53

28c 21b 592  9.30 1E (Hydro) 53a

28q 21c 537 10.28 1E 53b

28o 21c 607  7.59 2F 53c

28p 21b 608  7.47 2F 53d

28p 21c 608  7.59 2F 53e

28q 21b 537 10.32 1E 53f

28o 21b 608  7.59 2F 53g

28r 21c 523  9.18 1E (Hydro) 53h

35 21b 592  2.18 2Ha 53i

35 21c 592  2.17 2Ha 53j

36 21b 537 10.03 1E (Hydro) 53k

36 21c 537 10.05 1E (Hydro) 53l

35a 21c 662  2.30 2Ha 53m

35a 21b 662  2.29 2Ha 53n

35c 21c 554  1.96 2Ha 53o

35d 21b 608  2.06 2Ha 53p

35d 21c 608  2.07 2Ha 53q

35e 21b 624  2.08 2Ha 53r

35e 21c 624  2.09 2Ha 53s

35b 21b 646  2.29 2Ha 53t

35b 21c 646  2.29 2Ha 53u

28c 21f 580  9.33 1E (Hydro) 53v

28a 21f 526  8.85 1E (Hydro) 53w

28o 21f 596  9.5 1E (Hydro) 53x

28a 21g 596  7.75 2FF 53y

28c 21g 650  8.14 2FF 53z

35f 21b 568  1.9 2Ha 53aa

35f 21c 568  1.88 2Ha 53ab

35g 21b 622  2.04 2Ha 53ac

35g 21c 622  2.04 2Ha 53ad

35h 21b 638  2.06 2Ha 53ae

35h 21c 638  2.07 2Ha 53af

35i 21b 554  1.77 2Ha 53ag

35i 21c 554  1.77 2Ha 53ah

35j 21b 592  2.03 2Ha 53ai

35j 21c 592  2.03 2Ha 53aj*

— — 596  9.52 1E (Hydro) 53ak*

— — 596  9.53 1E (Hydro) 53al

28pa 21b 624  2.00 2Ha 53am

28pa 21c 624  1.99 2Ha *Ex 53aj and 53ak were obtained by chiral HPLCseparation of example 53w: Ex 53aj: Chiral HPLC (method 2Ja): R_(t) =13.35 min Ex 53ak: Chiral HPLC (method 2Ja): R_(t) = 15.28 min Relativestereochemistry of 3-fluoro-tetrahydro-pyran-4-ylamine assigned as cisby 1H-NMR.

Example 54

Example 30 (95 mg, 0.14 mmol), formaldehyde (0.027 ml, 0.34 mmol),N,N-diisopropyl-ethylamine (0.034 ml, 0.2 mmol) and trifluoroacetic acid(0.017 ml, 0.22 mmol) in 3 ml methanol were stirred at room temperaturefor 5 min Sodium cyanoborohydride (43 mg, 0.68 mmol) was added and thereaction mixture was stirred at room temperature overnight. The reactionmixture was concentrated under vacuum. 43 mg (0.08 mmol) of the desiredproduct were obtained as solid.

HPLC (Method 1E Hydro): R_(t). (min)=9.56

[M+H]⁺=552

The following example was synthesized in analogy to the preparation ofExample 54.

Ex Starting HPLC # STRUCTURE example [M + H]⁺ R_(t•) (min) Method 54a

53 606 7.53 2F

Example 55

To a solution of commercially available 3-pyrrolidin-3-yl-benzoic acidethyl ester (43.9 mg 0.2 mmol) in 0.2 DMA, a solution of Intermediate 43(40.7 mg, 0.1 mmol) in 0.3 ml of DMA and 0.08 ml of acetic acid wereadded. The reaction mixture was stirred at room temperature for 1 h,then, sodium triacetoxyborohydride (25.4 mg, 0.12 mmol) was added. Thereaction mixture was stirred at room tempertature for 18 h, then it waswarmed at 65° C. for 6 h. 0.4 ml of ethanol and 0.6 ml of an aqueous 10%sodium hydroxide solution were added and the reaction mixture wasstirred at 65° C. for 18 h. 0.5 ml of trifluoroacetic acid were addedand the reaction mixture was concentrated under vacuum. The mixture waspurified by reverse preparative LC/MS. 23 mg (0.04 mmol) of the desiredproduct were obtained.

HPLC (Method 2Ga): R_(t). (min)=1.34

[M+H]⁺=598

The following examples were synthesized in analogy to the preparation ofExample 55

Ex Inter- Amino- [M + HPLC Me- # STRUCTURE mediate ester Source H]⁺R_(t•) (min) thod 56

43 3- piperidin- 4yl- benzoic acid methyl ester Com- mercially available612 1.37 2Ga 57

43 3- piperidin- 3yl- benzoic acid methyl ester Com- mercially available612 1.35 2Ga 58

43 4- pyrrolidin- 3yl- benzoic acid methyl ester Com- merciallyavailable 598 1.33 2Ga 59

43 2- pyrrolidin- 3yl- benzoic acid methyl ester Com- merciallyavailable 598 1.46 2Gb 60

43 2,3- dihydro- spiro [indene- 1,4′- piperidine]- 3- carboxylic acidmethyl ester Com- mercially available 638 1.36 2Ga

1. A compound of formula (I),

wherein: R₁ is selected from —H, -halogen, —CN, —O—C₁-C₄-alkyl,—C₁-C₄-alkyl, —CH═CH₂, —C≡CH, —CF₃, —OCF₃, —OCF₂H, and —OCFH₂; R₇ is aring selected from —C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl, —C₅-C₁₀-aryl,and —C₅-C₁₀-heteroaryl, wherein the ring R₇ is optionally substitutedwith one or more groups selected from —CF₃, —O—CF₃, —S—CF₃, —CN,—C₁-C₆-alkyl,—C(CH₃)₂—CN, and -halogen, or wherein the ring R₇ isoptionally substituted with one or more groups selected from—C₁-C₆-alkyl, —O—C₁-C₆-alkyl, —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl,—C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl, —C₂-C₆-alkenyl, and—C₂-C₆-alkynyl, optionally being substituted by one or more groupsselected from —OH, —NH₂, —C₁-C₃-alkyl, —O—C₁-C₆-alkyl, —CN, —CF₃, —OCF₃,halogen, -methyl, and ═O, or wherein the ring R₇ is optionally furtherbi-valently substituted on two neighboring ring atoms, such that anannellated ring is formed by one or more groups selected from—C₁-C₆-alkylene, —C₂-C₆-alkenylene and —C₄-C₆-alkynylene, in which oneor two or three carbon centers may optionally be replaced by 1 or 2 or 3hetero atoms selected from N, O and S, the bivalent group beingoptionally substituted by one or more groups selected from —OH, —NH₂,—C₁-C₃-alkyl, —O—C₁-C₆-alkyl, —CN, —CF₃, —OCF₃, halogen, and ═O; R₂ isselected from —H, -halogen, —CN, —O—C₂-C₄-alkyl, —C₁-C₄-alkyl, —CH═CH₂,—C≡CH, —CF₃, —OCF₃, —OCF₂H, and —OCFH₂; R₃ is selected from —H, -methyl,-ethyl, -propyl, -i-propyl, -cyclopropyl, —OCH₃, —CF₃, and —CN; n is 1,2 or 3; G and E are independently selected from C—H or N; Z is C, and R₄and R₅ are independently selected from —H, —C₁-C₆-alkyl, —NH₂,—C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl, —C₅-C₁₀-aryl,—C₅-C₁₀-heteroaryl, and —C(O)—N(R₈,R_(8′)), with R₈ and R_(8′)independently being selected from —H, and —C₁-C₆-alkyl; or Z is N, andR₄ denotes an electron pair and R₅ is selected from —H, —C₁-C₆-alkyl,—NH₂, —C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl, —C₅-C₁₀-aryl,—C₅-C₁₀-heteroaryl, and —C(O)—N(R₈,R_(8′)), with R₈ and R_(8′)independently being selected from —H, and —C₁-C₆-alkyl; and R₄ and R₅ ifdifferent from an electron pair or —H are optionally independentlysubstituted with one or more groups selected from -halogen, —OH, —CF₃,—CN, —C₁-C₆-alkyl, —O—C₁-C₆-alkyl, —O—C₃-C₈-cycloalkyl,—O—C₃-C₈-heterocyclyl, —O—C₅-C₁₀-aryl, —O—C₅-C₁₀-heteroaryl,—C₀-C₆-alkylene-CN, —C₀-C₄-alkylene-O—C₁-C₄-alkyl,—C₀-C₄-alkylene-O—C₃-C₈-cycloalkyl,—C₀-C₄-alkylene-O—C₃-C₈-heterocyclyl, —C₀-C₄-alkylene-O—C₅-C₁₀-aryl,—C₀-C₄-alkylene-O—C₅-C₁₀-heteroaryl,—C₀-C₄-alkylene-Q-C₀-C₄-alkyl-N(R₉,R_(9′)),—C₀-C₄-alkylene-N(R₁₀)-Q-C₁-C₄-alkyl,—C₀-C₄-alkylene-N(R₁₀)-Q-C₃-C₈-cycloalkyl,—C₀-C₄-alkylene-N(R₁₀)-Q-C₃-C₈-heterocyclyl,—C₀-C₄-alkylene-N(R₁₀)-Q-C₅-C₁₀-aryl,—C₀-C₄-alkylene-N(R₁₀)-Q-C₅-C₁₀-heteroaryl,—C₀-C₄-alkylene-Q-N(R₁₁,R_(11′)),—C₀-C₄-alkylene-N(R₁₂)-Q-N(R₁₃,R_(13′)), —C₀-C₄-alkylene-R₁₄,—C₀-C₄-alkylene(R₂₀,R_(20′)), —C₀-C₄-alkylene-Q-C₁-C₆-alkyl,—C₀-C₄-alkylene-Q-C₃-C₈-cycloalkyl,—C₀-C₄-alkylene-Q-C₃-C₈-heterocyclyl, —C₀-C₄-alkylene-Q-C₅-C₁₀-aryl,—C₀-C₄-alkylene-Q-C₅-C₁₀-heteroaryl, —C₀-C₄-alkylene-O-Q-N(R₁₅,R_(15′)),and —C₀-C₄-alkylene-N(R₁₆)-Q-O-(R₁₇); wherein Q is selected from —C(O)—,and —SO₂—; R₁₀, R₁₂, R₁₆, are independently selected from —H,—C₁-C₆-alkyl, and —C₃-C₆-cycloalkyl, wherein R₉, R_(9′), R₁₁, R_(11′),R₁₃, R_(13′), R₁₅, R_(15′), are independently selected from —H,—C₁-C₆-alkyl, and —C₃-C₆-cycloalkyl, or R₉ and R_(9′), R₁₁ and R_(11′),R₁₃ and R_(13′), R₁₅ and R_(15′) together form a —C₂-C₆-alkylene group;R₁₄ and R₁₇ are independently selected from —H, —C₁-C₆-alkyl,—C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl, —C₃-C₈-cycloalkyl, and—C₃-C₈-heterocyclyl, wherein said —C₃-C₈-heterocyclyl optionallycomprises nitrogen and/or —SO₂— in the ring; wherein R₁₄ and R₁₇ areoptionally substituted with one or more groups selected from —OH, —OCH₃,—CF₃, —COOH, —OCF₃, —CN, -halogen, —C₁-C₄-alkyl, ═O, and—SO₂—C₁-C₄-alkyl; and R₂₀ and R_(20′) together form aspiro-C₃-C₈-carbocycle or spiro-C₃-C₈-heterocycle comprising one or moregroup selected from O in the ring, and wherein said spirocycle isoptionally further bi-valently substituted by an annellated ring forminggroup selected from —C₁-C₆-alkylene, —C₂-C₆-alkenylene, and—C₄-C₆-alkynylene and wherein said spirocycle is optionally furthersubstituted with one or more groups selected from —OH, —OCH₃, —CF₃,—COOH, —OCF₃, —CN, -halogen; or Z is C, and R₄ denotes —H and R₅ is agroup of the structure -L₁-R₁₈, wherein L₁ is selected from —NH—,—N(C₁-C₄-alkyl)-, and a bond, R₁₈ is selected from —C₅-C₁₀-aryl,—C₅-C₁₀-heteroaryl, —C₃-C₈-cycloalkyl, and —C₃-C₈-heterocyclyl, whereinR₁₈ is optionally substituted by one or more groups selected fromhalogen, —CF₃, —OCF₃, —CN, —OH, —O—C₁-C₄-alkyl, —C₁-C₆-alkyl,—NH—C(O)—C₁-C₆-alkyl, —N(C₁-C₄-alkyl)-C(O)—C₁-C₆-alkyl,—C(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl, —NH—S(O)₂—C₁-C₆-alkyl,—N(C₁-C₄-alkyl)-S(O)₂—C₁-C₆-alkyl, and —C(O)—O—C₁-C₆-alkyl, and R₄, R₅and R₁₈ are optionally further substituted by spiro-C₃-C₈-cycloalkyl orspiro-C₃-C₈-heterocyclyl such that together with R₄, R₅ and/or R₁₈ aspirocycle is formed, wherein said spiro-C₃-C₈-heterocyclyl optionallycomprises one or more groups selected from nitrogen, —C(O)—, —SO₂—, and—N(SO₂—C₁-C₄-alkyl)- in the ring; or R₄, R₅ and R₁₈ are optionallyfurther bi-valently substituted by one or more spirocyclic or annellatedring forming groups selected from —C₁-C₆-alkylene, —C₂-C₆-alkenylene,and —C₄-C₆-alkynylene, in which one or two carbon centers may optionallybe replaced by one or two heteroatoms selected from N, O and S and whichmay optionally be substituted by one or more groups on one ring atom oron two neighbouring ring atoms selected from —OH, —NH₂, —C₁-C₃-alkyl,—O—C₁-C₆-alkyl, —CN, —CF₃, —OCF₃, and halogen; and R₆ is selected from—H, —C₁-C₄-alkyl, —OH, —O—C₁-C₄-alkyl, -halogen, —CN, —CF₃, and —OCF₃;or an acid addition salt with a pharmacologically acceptable acid. 2.The compound of of claim 1, wherein: Z is C; and R₄ and R₅ areindependently selected from —H, -i-propyl, -amino, -pyrrolidinyl,-piperidinyl, -morpholinyl, -azepanyl, -oxazepanyl, -piperazinyl,-azetidinyl, -tetrahydropyranyl, -cyclopentyl, -cyclohexyl, and—C(O)—N(R₈,R_(8′)), wherein R₈ and R_(8′) are independently selectedfrom —H and —C₁-C₆-alkyl, and wherein R₄ and R₅ if different from —H areoptionally independently substituted with one or more groups selectedfrom -fluoro, -methyl, -ethyl, propyl, -i-propyl, -butyl, -i-butyl,-t-butyl, -hydroxy, —CF₃, —OCF₃, —CN, —O—CH₃, —O—C₂H₅, —O—C₃H₇, —CH₂—CN,—CH₂—O—CH₃, —(CH₂)₂—O—CH₃, —C(O)—CH₃, —C(O)—C₂H₅, —C(O)—C₃H₇, —COOH,—C(O)—NH₂, —C(O)—NH—CH₃, —C(O)—N(CH₃)₂, —NH—C(O)—CH₃, —N(CH₃)C(O)—CH₃,—NH—C(O)—C₂H₅, —N(CH₃)—C(O)—C₂H₅, —NH—C(O)—C₃H₇, —N(CH₃)—C(O)—C₃H₇,—NH—SO₂—CH₃, —N(CH₃)—SO₂—CH₃, —N(C₂H₅)—SO₂—CH₃, —N(C₃H₇)—SO₂—CH₃,—NH—SO₂—C₂H₅, —N(CH₃)—SO₂—C₂H₅, —N(C₂H₅)—SO₂—C₂H₅, —N(C₃H₇)—SO₂—C₂H₅,—NH—SO₂—C₃H₇, —N(CH₃)—SO₂—C₃H₇, —N(C₂H₅)—SO₂—C₃H₇, —N(C₃H₇)—SO₂—C₃H₇,—NH—SO₂—C₃H₅, —N(CH₃)—SO₂—C₃H₅, —N(C₂H₅)—SO₂—C₃H₅, —N(C₃H₇)—SO₂—C₂H₅,—CH₂—NH—SO₂—CH₃, —CH₂—N(CH₃)—SO₂—CH₃, —CH₂—NH—SO₂—C₂H₅,—CH₂—N(CH₃)—SO₂—C₂H₅, —CH₂—NH—SO₂—C₃H₇, —CH₂—N(CH₃)—SO₂—C₃H₇,—CH₂—NH—SO₂—C₃H₅, —CH₂—N(CH₃)—SO₂—C₃H₅, —NH—C(O)—NH₂, —N(CH₃)—C(O)—NH₂,—NH—C(O)—NH—CH₃, —N(CH₃)—C(O)—NH—CH₃, —NH—C(O)—N(CH₃)₂,—N(CH₃)—C(O)—N(CH₃)₂, —SO₂—NH₂, —SO₂—NH(CH₃), —SO₂—N(CH₃)₂,—C(O)—NH—C₂H₅, —C(O)—N(CH₃)—C₂H₅, —C(O)—N(CH₃)—C₃H₇, —C(O)—N(CH₃)—C₄H₉,—C(O)—NH—CH(CH₃)—C₂H₅, —C(O)—N(CH₃)—CH(CH₃)—C₂H₅, —CH₂—C(O)—NH₂,—CH₂—C(O)—NH—CH₃, —CH₂—C(O)—N(CH₃)₂, —N(CH₃)—SO₂—N(CH₃)₂,—(C₆-aryl)—COOH, -phenyl, -pyridin-4-yl, —CH₂-3-methyl-oxetan-3-yl,—O-1,2-difluoro-phen-5-yl, —O-pyridin-2-yl, -pyrrolidine-2-one-1-yl,-3,5-dimethyl-[1,2,4]triazol-4-yl, 3-methyl-[1,2,4]oxadiazol-5-yl,

or Z is C, and R₄ denotes —H and R₅ is a group of the structure -L₁-R₁₈,wherein L₁ is selected from —NH—, —N(CH₃)—, and —N(C₂H₅)—, and R₁₈ isselected from -tetrahydropyranyl, -cyclopropyl, -cyclobutyl,-cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl, -pyrrolidinyl,-piperidinyl, -piperazinyl, -morpholinyl, -chromanyl,-octahydro-pyrano-pyrrolyl, -octahydro-pyrano-pyridinyl,-octahydro-pyrano-oxazinyl, -oxaspirodecanyl, and-tetrahydro-naphthyridinyl, and R₁₈ is optionally substituted by one ormore groups selected from —F, —CF₃, —OCF₃, —CN, —OH, —O—CH₃, —CH₃,—NH—C(O)—CH₃, —N(CH₃)—C(O)—CH₃, —C(O)—CH₃, —S(O)₂—CH₃, —NH—S(O)₂—CH₃,—N(CH₃)—S(O)₂—CH₃, —N(CH₃)—S(O)₂—CH₂—CH₃, and —C(O)—O—C₂H₅; and R₄, R₅and R₁₈ are optionally further bi-valently substituted by one or moregroups selected from

on one ring atom or on two neighboring ring atoms, such that spirocyclicor annellated rings are formed.
 3. The compound of claim 1, wherein R₇is selected from —C₅-C₆-aryl, —C₅-C₆-heteroaryl, —C₃-C₈-cycloalkyl, and—C₃-C₈-heterocyclyl, wherein the ring R₇ is optionally substituted withone or more groups selected from —CF₃, —O—CF₃, —S—CF₃, —CN,-methyl,—C(CH₃)₂—CN, and -halogen.
 4. The compound of claim 1, whereinR₇ is selected from —C₅-C₆-aryl, and —C₅-C₆-heteroaryl, wherein the ringR₇ is optionally substituted with one or more groups selected from —CF₃,—O—CF₃, —S—CF₃, —CN, -methyl, —F, —Cl, —C(CH₃)₂—CN, and —Br.
 5. Thecompound of claim 1 wherein: Z is C; R₄ is —H; and R₅ is a group-L₁-R₁₈, wherein L₁ is selected from —NH—, —N(CH₃)—, —N(C₂H₅)—, and abond, and R₁₈ is selected from —C₆-heterocyclyl comprising 1 or 2 heteroatoms selected from N, and O, and R₁₈ is optionally substituted with oneor more groups selected from —F, —CF₃, —OCF₃, —CN, —OH, —O—CH₃, —CH₃,—NH—C(O)—CH₃, —N(CH₃)—C(O)—CH₃, —C(O)—CH₃, —S(O)₂—CH₃, —NH—S(O)₂—CH₃,—N(CH₃)—S(O)₂—CH₃, —N(CH₃)—S(O)₂—CH₂—CH₃, and —C(O)—O—C₂H₅; or R₄ and R₅are independently selected from —H, —C₁-C₆-alkyl, and —N(R₁₉,R_(19′)),wherein R₁₉ and R_(19′) together form a —C₂-C₆-alkylene group such thata ring is formed, wherein such ring is optionally substituted with oneor more groups selected from —F, —CF₃, —OCF₃, —CN, —OH, —O—CH₃, —CH₃,—NH—C(O)—CH₃, —N(CH₃)—C(O)—CH₃, —C(O)—CH₃, —S(O)₂—CH₃, —NH—S(O)₂—CH₃,—N(CH₃)—S(O)₂—CH₃, —N(CH₃)—S(O)₂—CH₂—CH₃, —(C₆-aryl)-COOH, —C(O)—O—C₂H₅,


6. The compound of claim 5 wherein: R₁₈ is optionally substituted withone or more groups selected from —F, —O—CH₃ and —N(CH₃)—S(O)₂—CH₃; andR₁₉ and R_(19′) together form a C₄-C₅ alkylene group such that a ring isformed, wherein such ring is optionally substituted with one or moregroups selected from from —O—CH₃, —NH—S(O)₂—CH₃, —(C₆-aryl)-COOH, and—N(CH₃)—S(O)₂—CH₃.


7. The compound of claim 6 wherein: R₁₈ is optionally substituted by—O—CH₃; and R₁₉ and R_(19′) together form a C₄-C₅ alkylene group suchthat a ring is formed, wherein such ring is optionally substituted with—N(CH₃)—S(O)₂—CH₃.
 8. The compound of claim 1, wherein R₂ is selectedfrom —H, -methyl, -ethyl, -propyl, -i-propyl, -butyl, -i-butyl,-t-butyl, —F, —Cl, —Br, —I, —CN, —CH═CH₂, and —C≡CH.
 9. The compound ofclaim 8, wherein R₂ is methyl.
 10. The compound of claim 8, wherein R₂is —H.
 11. The compound of claim 1, wherein R₃ is selected from —H,—CF₃, —O—CH₃, and -methyl.
 12. The compound of claim 11, wherein R₃ isH.
 13. The compound claim 11, wherein R₃ is —CF₃.
 14. The compound ofclaim 1, wherein R₆ is selected from —H, —CH₃, —C₂H₅, —O—CH₃, —O—C₂H₅,—F, —CF₃, and —OCF₃.
 15. The compound of claim 14, wherein R₆ isselected from —H and —O—CH₃.
 16. The compound of claim 1, wherein R₁ is—H.
 17. The compound of claim 1, wherein n is
 2. 18. The compound ofclaim 1, wherein G and E are N.
 19. The compound of claim 1, wherein Zis C.
 20. A method for the treatment of an inflammatory disease of therespiratory tract selected from chronic obstructive pulmonary disease,asthma, and cystic fibrosis, comprising administering an effectiveamount of a compound of claim 1 to a patient in need thereof.
 21. Amethod for the treatment of a neurologic disease selected frominflammatory and neuropathic pain, comprising administering an effectiveamount of a compound of claim 1 to a patient in need thereof.
 22. Amethod for the treatment of diabetes mellitus comprising administeringan effective amount of a compound of claim 1 to a patient in needthereof.
 23. A method for the treatment of peripheral atheroscleroticdisease comprising administering an effective amount of a compound ofclaim 1 to a patient in need thereof.
 24. A method for the treatment ofdiabetic nephropathy, comprising administering an effective amount of acompound of claim 1 to a patient in need thereof.